StemCell Therapy

You may get your hair color from your fathers side of the family and your great math skills from your mother. These traits are in the genes, so to speak. Likewise, longevity tends to run in familiesyour genetic make-up plays an important role in how you age. You can see evidence of this genetic connection in families with siblings who live into their 90s or families that have generation after generation of centenarians. These long-lived families are the basis for many genetic studies.

Identifying the genes associated with any trait is difficult. First, just locating the gene requires a detailed understanding of the trait, including knowledge of most, if not all, of the contributing factors and pathways related to that trait. Second, scientists must have clear ways of determining whether the gene suspected to have a relationship with the trait has a direct, indirect, or even no effect on that trait.

Identifying longevity genes is even more complex than determining genes for height or hair color, for example. Scientists do not know all the factors and pathways that contribute to longevity, and measuring a genes effect on long-lived animals, including humans, would literally take a lifetime! Instead, scientists have identified hundreds of genes that affect longevity in short-lived animal models, like worms and flies. Not all of these genes promote long life. Sometimes mutating or eliminating a gene increases lifespan, suggesting that the normal function of the gene limits longevity. Findings in animal models point to places for scientists to look for the genes that may influence longevity in humans.

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GENETICS: Is aging in our genes? - nia.nih.gov

Our story began in the 1970s with a young student in a lonely laboratory. So consumed with his work, he barely had time to attend to classes. So advanced, that his education was not found in books, but in the fabric of what makes us human: our DNA. His dedication is now legendary, and his work set in motion countless genetic discoveries, including the Human Genome Project, the first initiative to map all genes in the human genome. Today, Dr. George Church is a recognized giant in genetic science and one of the co-founders of Veritas Genetics. Along with an esteemed group of visionaries and scientists, including a few from Harvard Medical Schools Personal Genome Project, Church and Veritas Genetics have become the leader in genetic sequencing and interpretation. It took 10 years and nearly $3 billion dollars to sequence the first whole human genome. Now, were delivering it into the palm of your hand in a matter of weeks, all for less than half the cost of the average family vacation.

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Veritas Genetics - Committed to disease prevention, early ...

by Ben Best CONTENTS: LINKS TO SECTIONS BY TOPIC

Often we see people who smoke, don't exercise and eat all the wrong foods living to be a ripe old age. People tell us that it doesn't matter whether you smoke or are overweight, what matters is having good genes. Is this true?

The simple answer is that for every elderly person who is overweight, smokes, doesn't exercise, eats the wrong foods and doesn't take supplements there are many more who lived the same lifestyle and are in the cemetery (and who are therefore less visible). There are also many more people the same age who are living a more healthy lifestyle (emphasis on "living") and who are more healthy. Good heredity can protect you from bad living somewhat, but you are better off to live well.

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The longest, largest and most authoritative study on the effects of smoking upon health and longevity has followed the lives of nearly 35,000 British physicians since 1951[BRITISH MEDICAL JOURNAL; Doll,R; 328(7455):1519-1528 (2004)]. Although physicians may not seem representative of the population in general, their health histories and causes of death are very well documented.

Claims have been made that smokers die earlier than nonsmokers due to more risk-taking personalities, rather than because of the effects of tobacco. True enough, heavy smokers (over 25 cigarettes per day) in the study died of accidents, injury and poisoning more than twice as often as nonsmokers (in a couple of cases from fires started while smoking in bed). But these deaths accounted for less than 3% of total mortality.

According to the study, a heavy smoker is about 25 times more likely to die of lung cancer than a nonsmoker. And a light smoker (1 to 14 cigarettes per day) is about 8 times more likely to die of lung cancer. Similarly, a heavy smoker is about 24 times more likely to die of chronic obstructive pulmonary disease than a nonsmoker and a light smoker is about 9 times more likely. A similar relationship is seen for death rates from other forms of cancer and respiratory disease. This close relationship between fatal lung disease and smoking makes it difficult to deny that the smoke is directly damaging to the lungs.

On average, the nonsmokers lived about 10 more years than the smokers. For those born between 1920 and 1929 the death rate between the ages of 35 and 69 for nonsmokers was 15% and for smokers was 43% nearly three times greater. Of course, the smokers who survived beyond age 69 probably had better genes than those who did not, but they undoubtedly suffered more from respiratory disease and other forms of illness than the surviving nonsmokers.

The British physician study results are very similar to a survey of nearly a million American men and women by the American Cancer Society[AMERICAN JOURNAL OF PUBLIC HEALTH; Taylor,DH; 92(6):990-996 (2002)].

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(For more detail, see Health Benefits of Exercise)

Many studies have shown an association between exercise and reduced incidence of heart disease, adult onset diabetes and even cancer. A study of nearly 45,000 male health professionals showed that those who exercised in the highest 25% of intensity had a risk of coronary heart disease that was 70% that seen among the lowest 25%[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Tanasescu,M; 288(16):1994-2000 (2002)]. A study of nearly 22,000 male physicians showed that men who exercised 2 to 4 times weekly had 80% the stroke rate of those who exercised less than once per week[STROKE; Lee,IM; 30(1):1-6 (1999)]. A study of over 72,000 nurses showed that the fifth of women who exercised the most had 66% the stroke risk of the fifth who exercised the least. The middle fifth had 82% of the stroke risk of the fifth who exercised the least25%[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Hu,FB; 283(22):2961-2967 (2000)].

Diabetes increases the incidence of a variety of health conditions, including heart disease, neuropathy, kidney failure, etc. increasing the likelihood of an early death. In many ways diabetes exhibits the features of accelerated aging. "Type2 diabetes" also called "non-insulin-dependent diabetes" was formerly called "adult onset diabetes". But adolescents have increasingly been developing the disease. A Cincinnati study showed a ten-fold increase in adolescent type2 diabetes in the period between 1982 and 1994[THE JOURNAL OF PEDIATRICS; Pinhas-Hamiel,O; 128(5Pt1):608-615 (1996)]. There was not a ten-fold change in genetic makeup of adolescents in that period, but there was a great increase in adolescent obesity. A study of nearly 85,000 nurses concluded that obesity is the single most important factor leading to type2 diabetes in women[NEW ENGLAND JOURNAL OF MEDICINE; Hu,FB; 345(11):790-797 (2001)] (a result which is probably valid for men as well).

A study of nearly 22,000 male physicians showed that those who exercised more than 5times weekly had only 58% the incidence of type2 diabetes as those who exercised less than once per week. Those who exercised two to four times weekly had 62% the diabetes incidence and those who exercised once weekly had 77% the incidence[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Manson,JE; 268(1):63-67 (1992)]. Someone could argue that those who chose to exercise were those who are less likely to get diabetes, but a study which randomly assigned 3,234 non-diabetic persons to exercise at least 150 minutes per week or to not exercise showed those who exercised were only 58% as likely to get type2 diabetes as those who did not[NEW ENGLAND JOURNAL OF MEDICINE; Knowler,WC; 346(6):393-403 (2002)].

Even cancer risk might be reduced by exercise. An extensive review of the literature found a high relationship for both colorectal cancer and breast cancer with lack of exercise[CANCER CAUSES AND CONTROL; McTiernan,A; 9(5):487-508 (1998)]. Breast cancer and colorectal cancer are significantly influenced by diet as well as by exercise. A study in Italy found a correlation between these forms of cancer and the intake of saturated (but not polyunsaturated) fat[ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY; Favero,A; 492:51-55 (1999)].

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(For more detail, see Macronutrients, Dieting and Health)

A study of nearly 40,000 women health professionals found that the fifth who consumed the most dietary fiber had 46% the risk of myocardial infarction and 65% the total cardiovascular disease risk of the fifth consuming the least dietary fiber[JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY; Liu,S; 39(1):49-56 (2002)].

A study of Seventh Day Adventists showed that those who observed a vegetarian diet were at least four times less likely to have high blood pressure than those who ate meat[JOURNAL OF HYPERTENSION; Rouse,IL; 1(1):65-71 (2002)]. About a third of California Seventh Day Adventists are vegetarians, and those vegetarians have been shown to live 9.5 years (men) or 6.1 years (women) longer than other Californians. High blood pressure can cost 4.2 years (men) or 3.2 years (women) and diabetes (which is usually very susceptible to influence by diet) can cost 4.6 years (men) or 8.6 years (women)[ARCHIVES OF INTERNAL MEDICINE; Fraser,GE; 161(13):1645-1652 (2001)]. A prospective study of over half-a-million people found elevated mortality, cancer mortality and cardiovascular disease mortality in those who at red meat and processed meat (sausage, hot dogs, etc.)[ARCHIVES OF INTERNAL MEDICINE; Sinha,R; 169(6):562-571 (2009)].

The literature abounds with evidence that diets rich in fruits and vegetables reduce the risk of cancer and cardiovascular disease[JOURNAL OF POSTGRADUATE MEDICINE; Heber,D; 50(2):145-149 (2004)]. Diet certainly has an influential effect on longevity which is separable from heredity.

Caloric Restriction with Adequate Nutrition (CRAN) dramatically extends the maximum lifespan of laboratory animals. Rats, mice and hamsters experience maximum lifespan extension from a diet which contains 4060% of the calories (but all of the required nutrients) which the animals consume when they can eat as much as they want. Mean lifespan is increased over 50% and maximum lifespan is increased over 30%. There is evidence that humans on CRAN experience similar benefits. The experimental animals in these studies are compared to genetically-matched controls which eat freely and experience no life extension benefits. The dramatic diffenece in lifespan is due to diet, not genes.

The composition of protein, carbohydrate and fat in the diet can also significantly affect health and longevity. For details on this subject, see my essay Macronutrients, Dieting and Health.

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(For more detail, see Nutraceuticals Topic Index )

What about nutritional supplements? Poor nutrition is common, especially in the elderly. Supplements consisting of recommended dietary allowances of nutrients (plus extra VitaminE & beta-carotene) significantly improved the immune status of elderly subjects[THE LANCET 340:1124-1127 (1992)]. In fact, a randomized, double-blind placebo-controlled study of 200IU supplementation with alpha-tocopherol in persons over 65 years of age showed a 20% reduction in incidence of the common cold[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Meydani,SN; 292(7):828-836 (2004)].

In 1996 the JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION published the results of a multi-center, double-blind, randomized, placebo-controlled cancer prevention trial based on 200g/day selenium or placebo to 1,312 patients over a mean period of 4.5years[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Clark,LC; 276(24):1957-1963 (1996)]. The study reported a 50% decrease in total cancer incidence as well as a 63% reduction in prostate cancer, a 58% reduction in colorectal cancer and a 48% reduction in lung cancer. Only 6 of the 1,312 subjects had selenium blood levels below that achievable by the RDA prior to supplementation. Not only was this study a powerful refutation of the claim that dietary supplements are of no benefit, but its results were so impactful that it would be unethical for anyone to repeat it. After extensive scrutiny of the data only the evidence for reduction of prostate cancer is now accepted as statistically significant (for a 42% reduction in prostate cancer). The data still shows a total cancer mortality reduction of 51%[CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION; Duffield-Lillico,AJ; 11(7):630-639 (2002)].

It is worth noting the recent efforts of Dr. Bruce Ames to promote the use of supplements. Bruce Ames is most famous for the "Ames Test" which has allowed researchers to use bacteria rather than lab animals to screen for potential cancer-causing agents thus expediting the screening process. Dr. Ames says that it is unreasonable to expect that everyone (particularly the poor) is going to eat the recommended five servings of fruits and vegetables every day. He not only advocates a general vitamin and mineral supplement as an "insurance policy" to ensure getting the recommended minimums, but advises that recommended minimums are not sufficient to provide maximum protection from disease. And he notes the regenerative potential of taking supplements that combine lipoic acid with acetyl-L-carnitine[EMBO REPORTS; Ames,BN; 6(SpecNo):S20-S24 (2005)].

AntiOxidants and other supplements are excessively disparaged by some biogerontologists on the grounds that they do not increase maximum lifespan. But significantly increasing average age of death can be a gain in both life and health. The Nutraceuticals section of this website provides a great deal of evidence that nutritional supplements can improve health and thereby increase average lifespan ("square the curve").

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In Western countries, females live about 10% longer than males. Males have 4times as much oxidative DNA damage as females, presumably because females have more MnSOD and glutathione peroxidase[FREE RADICAL BIOLOGY & MEDICINE; Borras,C; 34(5):546-552 (2003)]. A 2002 study of centenarians in the United States found that female siblings were 8times more likely to reach age100 than cohorts born the same year and male siblings were 17times for likely to become centenarians themselves[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Perls,TT; 99(12):8442-8447 (2002)]. Mothers of persons who lived to at least 110years ("supercentenarians") were nearly six times more likely to have lived to age90 than females in the general population[JOURNAL OF GERONTOLOGY; Perls,T; 62A(9):1028-1034 (2007)]. Studies of centenarian populations have found quite a number of longevity-associated genotypes[PLoS GENETICS; Martin,GM; 3(7):e125 (2007)].

Children of older fathers (within the age range 25 to 45) were found to have longer telomeres and greater resistance to mortality from aging-associated diseases[AGING CELL; Unryn,BM; 4(2):97-101 (2005)]. A ten-year study of Danish twins aged 73-94 found a positive correlation between leucocyte telomere length and expected lifespan[AMERICAN JOURNAL OF EPIDEMIOLOGY; Kimura,M; 167(7):799-806 (2008)]. Studies of sperm from young(<30years) and old(>50years) donors found that sperm telomerase length increases with age[PLOS GENETICS; Kimura,M; 4(2):e37 (2008)].

Male sperm are produced throughtout life, whereas a woman typically produces few, if any, new egg cells during her reproductive years. For this reason, a mother typically passes about 14mutations to her offspring, whereas a father will pass about 40mutations at age20 and 80mutations at age40. Mutations in the father increase exponentially with age, doubling about every 16.5years[NATURE;Kong,A; 488:471-475 (2012)]. Risk of diseases such as autism and schizophrenia in offspring rise with increasing age of the father[Ibid.].

The cause of death for a sample 143 people over the age of 60 with shorter telomeres was found to be several times greater for heart disease and infectious diseases, but not for cancer[THE LANCET; Cawthon,RM; 361:393-395 (2003)]. Another study showed a significant correlation between telomere shortening and cognative impairment in elderly subjects[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Canela,A; 104(12):5300-5305 (2007)]. Yet another study found an inverse relationship between telomere length and pulse pressure, indicating a possible direct relationship between vascular aging and telomere length[HYPERTENSION; Jeanclos,E; 36(2):195-200 (2000)]. In a cohort of coronary artery disease outpatients the rate of telomere shortening was inversely related to blood levels of omega-3 polyunsaturated fatty acids[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Farzaneh-Far,R; 303(3):250-257 (2010)]. Higher levels of oxidative stress due to environmental factors increase the rate of telomere shortening[TRENDS IN BIOCHEMICAL SCIENCES 27(7):339-344 (2002)]. Psychological stress may be one of the environmental factors[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Epel,ES; 101(49):17312-17315 (2004)]. A study of 175 elderly Swedish twin-pairs found that the twins with the shortest telomeres (75% of the cohort) had 3times the risk of death compared to the 25% with the longest telomeres[AGING CELL; Bakaysa,SL; 6(6):769-774 (2007)].

Identical twins (monozygotic twins) have the same heredity (identical genes), so differences in the health and longevity of identical twins can only be due to environmental factors. Of course, identical twins typically have similar environments. Fraternal twins are also born together, are no closer genetically than other siblings, and have environments which are probably as similar as those shared by identical twins. Thus, comparing identical twins with fraternal twins can be a way of determining which effects are due to heredity and which are due to lifestyle (environment).

A study of Scandinavian twins found that if a female lived to be at least 92years, a fraternal twin had 1.57 the chance of doing so, and an identical twin was 2.5times more likely to do so than other females. For males, a fraternal twin was 1.76times as likely to reach 92 and an identical twin was 4.83times as likely[HUMAN GENETICS; Hjelmborg,J; 119(3):312-321 (2006)].

Both fraternal and identical twins show correlated levels of the inflammatory cytokines Tumor Necrosis Factor-alpha(TNF) and IL6 which play a role in diabetes and metabolic syndrome indicative of the influence of a common environment, including the intrauterine environment. Nonetheless, elderly twins show a strong genetic component to their plasma TNF levels[DIABETOLOGIA; Grunnet,L; 49(2):343-350 (2006)]. A study of 80-year-olds found that serum IL6 levels predicted mortality for both males & females, but TNF only predicted mortality for males[CLINICAL &; EXPERIMENTAL IMMUNOLOGY; Bruunsgaard,H; 132(1):24-31 (2003)]. But another study found serum TNF to predict mortality in centenarians, whereas IL6, IL8 and CRP did not[AMERICAN JOURNAL OF MEDICINE; Bruunsgaard,H; 115(4):278-283 (2003)].

Female centenarians are significantly more likely to have a gene that reduces IGF1 receptor signalling[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Suh,Y; 105(9):3438-3442 (2008)]. Two copies of a FOXO3A allele tripled the odds of becoming a centenarian in a Japanese-American cohort[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Willcox,BJ; 105(37):13987-13992 (2008)].

A long-term study of twins in Denmark showed that when one fraternal twin had a fatal stroke, there was a 10% chance that the other fraternal twin would die of stroke. But for identical twins there was an 18% chance that the second twin would also die of a stroke[STROKE; Bak,S; 33(3):769-774 (2002)]. The fact that identical twins (who have exactly the same genes) would be nearly twice as likely to have a stroke as fraternal twins (who are no closer genetically than any brother or sister) indicates that heredity does play a role in the likelihood of having a stroke. Nonetheless, the fact that when one of two genetically identical twins has a stoke that there is a less than 20% chance that the second genetically identical twin will have a stroke indicates that at least 80% of the chance of having a stroke is due to environmental (lifestyle) factors.

The Framingham Longevity Study showed that age at death can be predicted much better by Coronary Heart Disease (CHD) risk factors than risk factors for stroke or cancer[JOURNAL OF CLINICAL EPIDEMIOLOGY; Brand,FN; 45(2):169-174 (1992)]. A study of nearly 21,000 Swedish twins[JOURNAL OF INTERNAL MEDICINE; 252(3):247-254 (2002)] showed that when one male twin died of CHD there was a 57% likelihood that the other male twin would also die of CHD. Insofar as only about 20% of males normally die of CHD (roughly half of all male deaths due to cardiovascular disease are due to CHD), 57% represents nearly 3 times the frequency that would be expected between randomly selected pairs of men. Although this represents a significant role for heredity in CHD death for men, the fact that 43% of male twins die of causes different from the CHD that killed the first twin indicates a significant role for lifestyle in causing CHD death.

For female twins only in 38% of cases did the second twin die of CHD when the first twin had died of CHD. This would seem to indicate that for women, lifestyle rather than heredity more strongly influences the chance of dying from CHD than is the case for men. However, the study noted that the older twins were when they died, the less likely it would be for both twins to die of the same cause. In other words, the longer you live, the more your cause of death will be determined by your lifestyle rather than by your heredity. Women normally live longer than men, so by dying at a greater age their causes of death are more influenced by lifestyle and less influenced by heredity than is the case for men. If men had lived longer, we would expect greater differences in cause of death between the male twins.

Divergence of twins with age is not only evident in lifestyle factors such as smoking, exercise, diet and environment, but in gene expression. A study which compared 3-year-old identical twins with 50-year-old identical twins found that the younger twins were very epigenetically similar, whereas the older twins were very distinct in epigenetic expression[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Fraga,MF; 102(30):10604-10809 (2005)]. A study on mice showed that alterations in epigenetic expression with age may be up to two orders of magnitude greater than somatic mutations[GENETICS; Bennett-Baker,PE; 165(4):2055-2062 (2003)].

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Good genes do make a difference in being healthy and living long, but lifestyle choices usually make a bigger difference. And the longer we life, the more our remaining longevity depends upon our lifestyle rather than on our genes. The choice is not between quantity (long life) and quality (good health), because good health is usually a requirement for living long. Whether your genes are good or bad, you will probably be more healthy as well as live longer by not smoking, by exercising and by eating a good diet (which can be augmented by supplements).

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Is Longevity Entirely Hereditary? - BEN BEST

Healthy aging and longevity in humans are modulated by a lucky combination of genetic and non-genetic factors. Family studies demonstrated that about 25% of the variation in human longevity is due to genetic factors. The search for genetic and molecular basis of aging has led to the identification of genes correlated with the maintenance of the cell and of its basic metabolism as the main genetic factors affecting the individual variation of the aging phenotype. In addition, studies on calorie restriction and on the variability of genes associated with nutrient-sensing signaling, have shown that ipocaloric diet and/or a genetically efficient metabolism of nutrients, can modulate lifespan by promoting an efficient maintenance of the cell and of the organism. Recently, epigenetic studies have shown that epigenetic modifications, modulated by both genetic background and lifestyle, are very sensitive to the aging process and can either be a biomarker of the quality of aging or influence the rate and the quality of aging.

On the whole, current studies are showing that interventions modulating the interaction between genetic background and environment is essential to determine the individual chance to attain longevity.

The research on aging, and in particular the search for the determinants of successful aging and longevity, has been continuously growing in the last decades also due to the social and medical burden correlated to the continuous increase of lifespan in western countries and the consequent grow of the elderly population. One of the main questions in this field is the correlation between the genetic background and lifestyle in determining the individual chance of a delayed aging (possibly without age-related diseases and disabilities) and longevity. The results obtained by biogerontologists in these years, which highlighted most of the biological and biochemical mechanisms involved in the aging process, allowed to better understand such correlation. This has brought to elaborate important strategies focused on possible interventions to improve lifestyle in order to increase the chance to attain longevity by modulating the basic molecular mechanisms of aging.

Before the 1990ies it was largely spread the idea that aging is ineluctable and that genetics does not control it. It was important, in this view, the idea that aging occurs after reproduction, and then there is no need, but also no opportunity, for selection to act on genes that are expressed during this late period of life [1].

The researcher who pioneered the genetics of aging and longevity was Tom Johnson, who studied groups of C. elegans where he was able to separate long living individuals from short living subjects. The analysis of hybrids obtained from different strains of C. elegans, allowed to estimate that the heritability of life-span was between 20 and 50% [2, 3]. Subsequently, he started the analysis of different mutants and, with M. Klass, found a number of mutants with longer lifespan. Subsequently, Tom Johnson found out that most of the mutants with long lifespan had mutations in the age1 gene [4]. This gene turned out to be the catalytic subunit of class-I phosphatidylinositol 3-kinase (PI3K).

The studies of Johnson clearly demonstrated that genetic variability could indeed affect lifespan. This triggered many studies in model organisms in order to disentangle the different biochemical pathways which could affect lifespan, and to highlight the genes coding for the proteins involved in such pathways. In particular, yeast, C. elegans, drosophila and mice were analyzed and this highlighted numerous genes which could affect lifespan if mutated (for an updated list of these genes see http://genomics.senescence.info/genes/models.html). Most of these genes are related to the maintenance of the integrity of the cell (especially the integrity of DNA). In C. elegans, however, some of the main genes which have been found to modulate lifespan (daf2, daf16) are related to the ability to enter the dauer status [5, 6], that is a quiescent status (usually entered in case of nutrient deprivation) with a minimum energy expense, which causes an arrest of the reproduction process and allows the organism to live longer expecting for the availability of nutrients. This suggested that longevity can be attained by means of an efficient maintenance of the cell but also by diverting resources from reproduction to self maintenance, in line with previous findings that dietary restriction can extend lifespan. After the characterization of these genes in C. elegans, it was found that in mice the ortholog of daf16 (FOXO) could affect lifespan. In mammals, FOXO is correlated to the Insulin/IGF1 axis which is stimulated by nutrient availability and, through FOXO, promotes protein synthesis [711].

It is of note that some Authors suggested these molecular mechanisms modulating lifespan could be due to a pleiotropic effect of genes which have evolved for different purposes (such as the genes in the IGF-1 pathway which have evolved to face presence/absence of nutrients) but can, ultimately affect lifespan; others proposed that some genes may have evolved to program aging and avoid immortality, as this would hamper the continuous substitution of old subjects with new, younger, ones [12, 13].

It was obviously inevitable that the research of the genetic basis of longevity turned to human beings and investigated whether the common genetic variability of human populations could affect inter individual differences in lifespan but also whether the genes found to prolong lifespan in model organisms, on turn, were correlated to human lifespan.

As to the first question (does common genetic variability affect lifespan, and in particular does it affect longevity?), this has been studied by two approaches. The first one was the reconstruction of the sibships of long-lived subjects [14, 15] and the comparison of their survival curves with those of the birth cohorts born in the same geographical area. This approach demonstrated that brothers and sisters of the long-lived subjects had a clear survival advantage (at any age) with respect to the general population. The second approach, with intrafamily controls, was started in order to distinguish the genetic from the familiar effect. Montesanto et al. [15] compared the survival function of brothers of centenarians with those estimated for their brothers in law, that is with the men who married their sisters; these men were supposed to share with the brothers of the long lived subjects the familiar environment. By using this second approach, it has been found that the survival advantage of siblings of long-lived subjects was not completely shared by their brothers in law, despite they shared the same environment for most of their life. This suggested that beyond the family environment, there are genetic factors influencing survival and, consequently, lifespan. Interestingly, in this study, the survival curve of the sisters of long-lived subjects did not differ from the one of sisters in law, suggesting that the genetic component does explain lifespan in men more than in women. The genetic component of lifespan in humans has also been analyzed by comparing the age of death of monozygotic and dizygotic twins. This has allowed to estimate that about 25% of the variation in human longevity can be due to genetic factors and indicated that this component is higher at older ages and is more important in males than in females [1618].

In parallel to these studies, many researches have been carried out to search the genetic variants responsible of modulating human longevity. Most of them were carried out by a case/control approach, by comparing the frequency of specific polymorphisms in long-lived subjects and in younger geographically matched controls. The rationale of this study design is that as the population ages, alleles favorable for survival will be present at higher frequency among long-living people, while unfavorable alleles will be eliminated [1921]. The candidate genes analyzed by this approach were either genes involved in age-related diseases (such as APOE, which had been observed to be involved in the predisposition to Alzheimer Disease and other age-related cognitive impairments), or genes implicated in pathways related to longevity in studies with model organisms (IGF-1, FOXO, Sirtuins) [2225]. This study design has indeed led to find numerous polymorphic genes the variability of which affects longevity. However, each of these polymorphisms turned out to explain only a very small fraction of the longevity variability. Indeed high-throughput Genome-wide analyses, which have recently been carried out have identified many genes positively associated with longevity but only a very few ones could hold multiple test significance and successfully replicated in different studies and across different populations [2629]. Population stratification and inadequate sample sizes are among the main plausible explanations [30]. The adoption of innovative study design and the development of new statistical and computational tools for effective processing of genetic data arising from high-throughput DNA technologies will help to better understand the complex genetic architecture underlying human longevity [31, 32].

A new way of looking at the genetic data has been proposed by Raule et al. [33] who analyzed the complete sequences of mitochondrial DNA from long-lived subjects coming from different areas of Europe. The availability of complete sequences allowed to evaluate for the first time the cumulative effects of specific, concomitant mitochondrial DNA (mtDNA) mutations, including those that per se have a low, or very low, impact. The analysis indicated that the presence of single mutations on mtDNA complex I may be beneficial for longevity, while the co-occurrence of mutations on both complexes I and III or on both I and V might lower the individuals chances for longevity. Previous analyses on single mutations falling on complex I (either specific mutations or mutations defining groups of haplotypes) had given contrasting results, showing association with longevity in some cases but not in others. It is likely that positive results were obtained in populations were mutations on complex I were not associated with mutations on complex III or V, while negative results were obtained in populations with high prevalence of mtDNA haplotypes carrying mutations on complex I in association with mutations in complex III and V. This approach confirmed that most of the genetic variants have a very limited effect on longevity, and that only their cumulative effect can give a consistent appreciable effect and suggests that a limit of previous analyses has been to search for single mutations instead of cumulative effects. On the other hand, it is very difficult to think of using such approach, which has been successful for mitochondrial DNA, on genomic DNA unless small fractions (or specific regions harboring genes involved in relevant pathways) are analyzed.

On the whole, the genetic association studies suggested that, also in humans, mutations in genes correlated with the maintenance of the cell and of its basic metabolism are essential in modulating lifespan. Indeed, genes involved in DNA repair [34], telomere conservation [3537], heat shock response [38, 39], and the management of free radicals levels [33, 40] were found to contribute to longevity or, in case of reduced functionality, to accelerated senescence (cellular aging) and the consequent organism aging. In addition, as suggested by the studies in mice, the pathways involved in nutrient-sensing signaling and in regulating transcription, such as IGF-1/insulin axis [41] and TOR (target of rapamycin) [42] showed to be involved in modulating human longevity. Besides these genes involved in cellular maintenance/metabolism and senescence, concurrent efforts, especially from clinical studies, also showed that genes implicated in important organismal process may have a strong impact on aging and longevity. For instance genes involved in lipoprotein metabolism (especially APOE), cardiovascular homeostasis, immunity, and inflammation have been found to play an important role in aging, age-related disorders, and organism longevity [4346].

Life expectancy at birth has been increasing for most of the last century in western societies, thanks to the continuous amelioration of medical assistance, to the improvement of the environment (in particular clean, safe water and food), and to the improvement of nutrients. For instance, in Italy life expectancy went from 29years in 1861 to 82 in 2011 (Table

reports the evolution of this data in women and men). Similarly, the extreme longevity has been growing in these years. Indeed, the number of centenarians (still in Italy) remarkably increased from 165 in 1951 to more than 15000 in 2011. These results have been attained first by a dramatic reduction of infectious diseases, which, on turn, has dramatically reduced infantile mortality, but also mortality in adult age. In fact, in 2011 less than 10% of deaths occurred in subjects under 60years of age, while the corresponding figures were 74% in 1872, 56% in 1901 and 25% in 1951. However, in the last decades, the continuous extension of lifespan was mainly due to the improvement of medical assistance with respect to age-related diseases, especially Cardiovascular Diseases and Cancer, which allowed to increase lifespan of 5years in the last 2 decades and of 2years in the last 10years (data from

and

).

Evolution of lifespan expectancy in Italy from 1861

1861

28

29

29

1871

30

31

30

1881

35

35

35

1891

38

39

38

1901

43

43

43

1911

46

46

46

1921

48

50

49

1931

53

56

55

1941

55

58

56

1951

63

67

65

1961

67

72

69

1971

69

75

72

1981

71

78

75

1991

74

80

77

2001

77

83

80

2011

79

84

82

These data clearly show that environmental factors have a very strong impact on lifespan and on longevity in humans. However, the extension of lifespan that there has been in the last decades have not been accompanied by a similar extension of healthy lifespan. Indeed, in most cases this lifespan extension is due to the chronicit of the age-related diseases. This has brought the community of biogerontologists to study interventions, possibly modulated on the knowledge emerged from the studies on the genetic and biomolecular basis of longevity, to extend not only lifespan but also healthy lifespan, or, with a new word, healthspan. In fact, model organisms with mutations that extend lifespan have a healthy life also when they are old. This suggested that health span extension could be attained by targeting (stimulating or silencing) the genes, which had been highlighted to be involved in life extension in both model organisms and humans [47]. In support of this hypothesis, it has been reported that dietary restricted mice, which live much longer and show a very delayed aging phenotype than mice fed at libitum, at old age have an expression pattern very different from mice of the same age for a number of genes correlated with life extension, such as those related to DNA repair, stress response, immune response and others [48, 49]. Thus, dietary restriction can trigger a molecular-genetic response which postpones aging and age-related phenotypes. This has brought to search for drugs or interventions which may act on these mechanisms without the side effects of calorie restriction. Among the most important interventions which have been considered in this context, we may name the protein restriction, the use of drugs targeting different genes of IGF-1 axis or of the FOXO/TOR pathway [47]. In addition, these studies have allowed to reconsider previous data on some areas characterized by exceptional longevity (such as Okinawa, Sardinia and Calabria) which are characterized by traditional ipoproteic diets, such as the Mediterranean diet [5053]. In these cases, then, the environment, that is the traditional diet, has allowed to stimulate the molecular mechanisms which can increase life span.

Among the several changes that occur with the aging process, in the last decade Epigenomics has attracted the interest of many researchers. This was mainly due to the fact that epigenetic modifications summarizing, at least in part, the interaction between the individual genetic background and lifestyle characteristics, should be potentially able to capture part of the unexplained susceptibility observed today for complex diseases (the so-called missing heritability problem).

Starting from the pioneeristic observations that epigenetic modifications affect not only the aging process but also its quality (successful aging) [54], EpiGenome-Wide Association Studies identified hundreds of sites spread along the entire genome in which methylation levels change between oldest old and younger subjects. In particular, Horwat and co-workers, on the basis of the methylation levels of 353 CpG units, formulated a mathematical model, the so-called epigenetic clock, that showed some important properties [55]. First, it was able predict the chronological age of a subject starting from the methylation level of several cells and tissues of his body. Second, it represents one of the most accurate biomarker of age (also superior to the estimates obtained from the telomere length). Third, using methylation levels of blood and brain tissues from subjects affected by Down syndrome, it showed that an accelerated aging occur in such a syndrome [56]. Fourth, it was able to predict all-cause mortality also after adjusting for traditional risk factors [57]. Finally, when it was used to estimate the biological age of several tissues from supercentenarians, it has been demonstrated that brain and muscle represent the youngest tissues of these exceptional individuals [58].

However, even if the cause-effect relationship between methylation process and aging is still not clear, the potential applications of this discovery are very wide, ranging from detailed monitoring of changes occurring with age within individual systems or organs (muscle, brain, etc.) to forensic purposes. For this and several other reasons, future advances in this field could help the understanding of the complex physiology of aging, lifespan and age-associated diseases.

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Human longevity: Genetics or Lifestyle? It takes two to ...

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Posted on April 9, 2014 by Dan Buettner

By Dan Buettner

Life expectancy of an American born today averages 78.2 years. But this year, over 70,000 Americans have reached their 100thbirthday. What are they doing that the average American isnt (or wont?)

To answer the question, we teamed up with National Geographic to find the worlds longest-lived people and study them. We knew most of the answers lied within their lifestyle and environment (The Danish Twin Study established that only about 20% of how long the average person lives is determined by genes.). Then we worked with a team of demographers to find pockets of people around the world with the highest life expectancy, or with the highest proportions of people who reach age 100.

We found five places that met our criteria:

We then assembled a team of medical researchers, anthropologists, demographers, and epidemiologists to search for evidence-based common denominators among all places. We found nine:

1. Move NaturallyThe worlds longest-lived people dont pump iron, run marathons or join gyms. Instead, they live in environments that constantly nudge them into moving without thinking about it. They grow gardens and dont have mechanical conveniences for house and yard work.

2. Purpose. The Okinawans call it Ikigai and the Nicoyans call it plan de vida; for both it translates to why I wake up in the morning. Knowing your sense of purpose is worth up to seven years of extra life expectancy

3. Down Shift Even people in the Blue Zones experiencestress. Stress leads to chronic inflammation, associated with every major age-related disease. What the worlds longest-lived people have that we dont are routines to shed that stress. Okinawans take a few moments each day to remember their ancestors, Adventists pray, Ikarians take a nap and Sardinians do happy hour.

4. 80% Rule Hara hachi bu the Okinawan, 2500-year old Confucian mantra said before meals reminds them to stop eating when their stomachs are 80 percent full. The 20% gap between not being hungry and feeling full could be the difference between losing weight or gaining it. People in the Blue Zones eat their smallest meal in the late afternoon or early evening and then they dont eat any more the rest of the day.

5. Plant Slant Beans, including fava, black, soy and lentils, are the cornerstone of most centenarian diets. Meatmostly porkis eaten on average only five times per month. Serving sizes are 3-4 oz., about the size of deck or cards.

6. Wine @ 5 People in all Blue Zones (except Adventists) drink alcohol moderately and regularly. Moderate drinkers outlive non-drinkers. The trick is to drink 1-2 glasses per day (preferably Sardinian Cannonau wine), with friends and/or with food. And no, you cant save up all weekend and have 14 drinks on Saturday.

7. Belong All but five of the 263 centenarians we interviewed belonged to some faith-based community. Denomination doesnt seem to matter. Research shows that attending faith-based services four times per month will add 4-14 years of life expectancy.

8. Loved Ones FirstSuccessful centenarians in the Blue Zones put their families first. This means keeping aging parents and grandparents nearby or in the home (It lowers disease and mortality rates of children in the home too.). They commit to a life partner (which can add up to 3 years of life expectancy) and invest in their children with time and love (Theyll be more likely to care for you when the time comes).

9. Right TribeThe worlds longest lived people choseor were born intosocial circles that supported healthy behaviors, Okinawans created moaisgroups of five friends that committed to each other for life. Research from the Framingham Studies shows that smoking, obesity, happiness, andeven loneliness are contagious.So the social networks of long-lived people have favorably shaped their health behaviors.

To make it to age 100, you have to have won the genetic lottery. But most of us have the capacity to make it well into our early 90s and largely without chronic disease. As the Adventists demonstrate, the average persons life expectancy could increase by 10-12 years by adopting a Blue Zones lifestyle.

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Power 9 - Blue Zones

Whether your father, mother or siblings have had heart disease may seem like the most important predictor of your own chances of a heart attack. Not so says a large Swedish study published in the Journal of the American College of Cardiology in 2014. In fact, it showed that 5 specific lifestyle factors like eating right, regular exercise and quitting smoking can combine to prevent 80% of first heart attacks.

The researchers, from the Karolinska Institute in Stockholm, set out to determine to what degree healthy habits individually - or in concert - help adults avoid a future heart attack, or myocardial infarction.

Rates of coronary heart disease have dropped in many parts of the world, write the authors, thanks to advances in medications that work to fight high blood pressure and lower cholesterol. Since huge populations are at risk of cardiovascular disease, however, the use of prescription drugs - with their own risks of side effects and significant cost if taken over the long term - are not an effective wide-scale preventative strategy, argue the researchers. They write that their own past research on women and that of other scientists on both genders shows lifestyle changes can dramatically cut heart attack risk.

What the study examined: Men between the ages of 45 and 79 were recruited in 1997, and surveyed about their eating and activity habits, along with data including their weight, family history of heart disease, and level of education.

A total of 20,721 men without any history of cardiovascular disease, cancer, or diabetes were then tracked over an 11-year period.

Five diet and lifestyle factors were examined: diet, smoking habits, alcohol consumption, belly fat and daily activity level.

What the researchers discovered: Each of the five lifestyle habits or conditions was found to offer its own individual benefit in preventing a future heart attack.

The best odds were found among men adhering to all five - reaping an 80% reduction in heart attack risk - although only 1% of the study population was in this category.

Here's how the habits ranked according to heart attack protection:

1. Quitting smoking (36% lower risk): Consistent with extensive previous research, quitting smoking is one of the top longevity-threatening habits you should abandon. In this Swedish trial, men who had either never smoked, or quit at least 20 years prior to the beginning of the study enjoyed a 36% lower chance of a first heart attack.

This jives with findings of many previous investigations including the Million Women Study in the UK, in which almost 1.2 million women were tracked over a 12-year period. That longitudinal research found that quitting by the age of 30 or 40 reaped an extra 11 years of life on average, thanks not only to fewer heart attacks, but less cancer and respiratory disease as well.

2. Eating a nutritious diet (20% lower risk): Again, no surprise that a healthy plant-based diet can help ward off a heart attack (and other age-related diseases like diabetes and cancer). The Swedish study characterized a healthy diet using the Recommended Food Score from the National Health and Nutrition Examination Survey (NHANES) in the US, which is "strongly predictive of mortality" and includes the following:

Those subjects who followed these guidelines most closely had a 20% lower risk of a first heart attack, even if they also ate foods from the "non-recommended" list such as red and processed meat, refined cereals and sweets.

3. Getting rid of belly fat (12% lower risk): Increasingly, epidemiologists are finding waist circumference and waist-to-hip ratio to be a better predictor of ill health than sheer body weight, especially when it comes to abdominal fat that surrounds your internal organs (visceral fat) and not just the pudge that sits under the skin of your belly making your waistband too tight.

Indeed, subjects in this Swedish study whose waistlines measured less than 95 cm (about 38") over the course of the trial, had a 12% lower risk of a first heart attack compared with men with more belly fat.

4. Drinking only in moderation (11% lower risk): In this study, drinking in moderation cut the risk of a first heart attack by about 11%. This is in line with very consistent evidence that consuming alcohol in moderation reduces the risk of cardiovascular disease, including heart attacks and stroke.

Still, the researchers offer certain reservations about alcohol's benefits, since as soon as consumption goes beyond light-to-moderate intakes of 1-2 drinks per day, there are far more hazards than benefits to health in the form of heart disease, cancer and accidents.

To recap: people who drink in moderation may be healthier than teetotalers, but only if they drink in moderation.

5. Being physically active (3% reduction in risk): Men who walked or cycled 40 minutes per day, and exercised at least one hour per week were found to have a 3% lower risk of a first heart attack in this study. That number is surprisingly low, considering other evidence that exercise is very beneficial for heart health. Still, exercise has such strong benefits not only for your cardiovascular system, but towards strengthening your bones, your respiratory system, helping ward off dementia and also stress relief (not to mention avoiding the hazards of sitting still), it should not be considered a fringe health strategy. The more you move, the better.

Wait - didn't this study just look at healthy men? These male subjects were all free of disease when the study launched in the late 1990s. A separate analysis was conducted among more than 7,000 men with hypertension and high cholesterol in 1997, which found that the risk reduction of each healthy behavior was similar to that of men without either condition.

Bottom line: Unlike your genetic makeup, diet, exercise and whether or not you smoke are all within your control; in science jargon, "modifiable lifestyle factors". Such changes may not always be easy to implement, but it can be inspiring to discover that what you do each day can play a greater role in determining your chances of a first heart attack than what you inherit.

In this large study, 86% of first heart attacks were avoided by the small proportion of men who adhered to all 5 healthy habits, regardless of family history of cardiovascular disease. Generalized to the greater population, that means 4 out of 5 first heart attacks might be prevented with straightforward and manageable lifestyle changes.

Get motivated to build healthy habits:

Sources:

Agneta kesson, Susanna C. Larsson, Andrea Discacciati, Alicja Wolk. "Low-Risk Diet and Lifestyle Habits in the Primary Prevention of Myocardial Infarction in Men: A Population-Based Prospective Cohort Study." Journal of the American College of Cardiology Volume 64, Issue 13, Pages A1-A24, 1299-1306 (30 September 2014)

Mozaffarian, Dariush. "The Promise of Lifestyle for Cardiovascular Health." Journal of the American College of Cardiology Volume 64, Issue 13, 1307-1309 (30 September 2014)

2016 About, Inc. All rights reserved.

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5 Ways to Prevent a First Heart Attack - Verywell

Summary: Researchers have identified a series of genes that could modulate the effect of mood and the response to stress on lifespan.

Source: Indiana University.

The visible impacts of depression and stress that can be seen in a persons face, and contribute to shorter lives, can also be found in alterations in genetic activity, according to newly published research.

In a series of studies involving both C. elegans worms and human cohorts, researchers from the Indiana University School of Medicine and the Scripps Research Institute have identified a series of genes that may modulate the effects of good or bad mood and response to stress on lifespan. In particular, the research pointed to a gene known as ANK3 as playing a key role in affecting longevity. The research was published May 24, 2016 in the journal Molecular Psychiatry.

We were looking for genes that might be at the interface between mood, stress and longevity, said Alexander B. Niculescu III, M.D., Ph.D., professor of psychiatry and medical neuroscience at the IU School of Medicine. We have found a series of genes involved in mood disorders and stress disorders which also seem to be involved in longevity.

Our subsequent analyses of these genes found that they change in expression with age, and that people subject to significant stress and/or mood disorders, such as people who completed suicide, had a shift in expression levels of these genes that would be associated with premature aging and reduced longevity said Dr. Niculescu, who is also attending psychiatrist and research and development investigator at the Indianapolis Veterans Affairs Medical Center.

The research began with studies in C. elegans, a worm widely used in life sciences research. An earlier study by one of the study co-authors, Michael Petrascheck, Ph.D., of the Scripps Research Institute, found that exposing C. elegans to the antidepressant mianserin, which is used to treat mood and stress disorders, extended the animals lifespan.

In the Molecular Psychiatry study, the researchers methodically conducted a series of analyses to discover, prioritize,

Adding genes that had scored nearly as high as ANK3 in the Convergent Functional Genomics analysis to create a panel of biomarkers showed similar but somewhat stronger results, particularly among those who had committed suicide. NeuroscienceNews.com image is for illustrative purposes only.

The authors said that these studies uncover ANK3 and other genes in our dataset as biological links between mood, stress and lifespan, that may be biomarkers for biological age as well as targets for personalized preventive or therapeutic interventions.

About this neuroscience research article

Additional investigators contributing to the research were Sunitha Rangaraju, Daniel R. Salomon and Michael Petrascheck of the Scripps Research Institute; Daniel F. Levey, Kwangsik Nho, Nitika Jain, Katie Andrews, Helen Le-Niculescu and Andrew J. Saykin of the Indiana University School of Medicine.

Funding: The research was supported by two National Institutes of Health Directors New Innovator Awards (1DP2OD007363 and 1DP2OD008398), as well as NIH U19 A1063603, NIH R00 LM011384 and IADC P30 AG010133.

Source: Eric Schoch Indiana University Image Source: This NeuroscienceNews.com image is in the public domain. Original Research: Abstract for Mood, stress and longevity: convergence on ANK3 by S Rangaraju, D F Levey, K Nho, N Jain, K D Andrews, H Le-Niculescu, D R Salomon, A J Saykin, M Petrascheck & A B Niculescu in Molecular Psychiatry. Published online May 24 2016 doi:10.1038/mp.2016.65

Cite This NeuroscienceNews.com Article

Indiana University. Genes Linked to the Effect of Stress and Mood on Longevity Identified. NeuroscienceNews. NeuroscienceNews, 24 May 2016. <http://neurosciencenews.com/mood-longevity-genetics-4285/>.

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Abstract

Mood, stress and longevity: convergence on ANK3

Antidepressants have been shown to improve longevity in C. elegans. It is plausible that orthologs of genes involved in mood regulation and stress response are involved in such an effect. We sought to understand the underlying biology. First, we analyzed the transcriptome from worms treated with the antidepressant mianserin, previously identified in a large-scale unbiased drug screen as promoting increased lifespan in worms. We identified the most robust treatment-related changes in gene expression, and identified the corresponding human orthologs. Our analysis uncovered a series of genes and biological pathways that may be at the interface between antidepressant effects and longevity, notably pathways involved in drug metabolism/degradation (nicotine and melatonin). Second, we examined which of these genes overlap with genes which may be involved in depressive symptoms in an aging non-psychiatric human population (n=3577), discovered using a genome-wide association study (GWAS) approach in a design with extremes of distribution of phenotype. Third, we used a convergent functional genomics (CFG) approach to prioritize these genes for relevance to mood disorders and stress. The top gene identified was ANK3. To validate our findings, we conducted genetic and gene-expression studies, in C. elegans and in humans. We studied C. elegans inactivating mutants for ANK3/unc-44, and show that they survive longer than wild-type, particularly in older worms, independently of mianserin treatment. We also show that some ANK3/unc-44 expression is necessary for the effects of mianserin on prolonging lifespan and survival in the face of oxidative stress, particularly in younger worms. Wild-type ANK3/unc-44 increases in expression with age in C. elegans, and is maintained at lower youthful levels by mianserin treatment. These lower levels may be optimal in terms of longevity, offering a favorable balance between sufficient oxidative stress resistance in younger worms and survival effects in older worms. Thus, ANK3/unc-44 may represent an example of antagonistic pleiotropy, in which low-expression level in young animals are beneficial, but the age-associated increase becomes detrimental. Inactivating mutations in ANK3/unc-44 reverse this effect and cause detrimental effects in young animals (sensitivity to oxidative stress) and beneficial effect in old animals (increased survival). In humans, we studied if the most significant single nucleotide polymorphism (SNP) for depressive symptoms in ANK3 from our GWAS has a relationship to lifespan, and show a trend towards longer lifespan in individuals with the risk allele for depressive symptoms in men (odds ratio (OR) 1.41, P=0.031) but not in women (OR 1.08, P=0.33). We also examined whether ANK3, by itself or in a panel with other top CFG-prioritized genes, acts as a blood gene-expression biomarker for biological age, in two independent cohorts, one of live psychiatric patients (n=737), and one of suicide completers from the coroners office (n=45). We show significantly lower levels of ANK3 expression in chronologically younger individuals than in middle age individuals, with a diminution of that effect in suicide completers, who presumably have been exposed to more severe and acute negative mood and stress. Of note, ANK3 was previously reported to be overexpressed in fibroblasts from patients with HutchinsonGilford progeria syndrome, a form of accelerated aging. Taken together, these studies uncover ANK3 and other genes in our dataset as biological links between mood, stress and longevity/aging, that may be biomarkers as well as targets for preventive or therapeutic interventions. Drug repurposing bioinformatics analyses identified the relatively innocuous omega-3 fatty acid DHA (docosahexaenoic acid), piracetam, quercetin, vitamin D and resveratrol as potential longevity promoting compounds, along with a series of existing drugs, such as estrogen-like compounds, antidiabetics and sirolimus/rapamycin. Intriguingly, some of our top candidate genes for mood and stress-modulated longevity were changed in expression in opposite direction in previous studies in the Alzheimer disease. Additionally, a whole series of others were changed in expression in opposite direction in our previous studies on suicide, suggesting the possibility of a life switch actively controlled by mood and stress.

Mood, stress and longevity: convergence on ANK3 by S Rangaraju, D F Levey, K Nho, N Jain, K D Andrews, H Le-Niculescu, D R Salomon, A J Saykin, M Petrascheck & A B Niculescu in Molecular Psychiatry. Published online May 24 2016 doi:10.1038/mp.2016.65

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AgingAlzheimer's diseaseANK3emotionGeneticsGoldilocks effectHutchinson-Gilford progeria syndromelongevitymitochondriamoodPsychologystresssuicide

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Genes Linked to the Effect of Stress and Mood on Longevity ...

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By: Mike Mahler

Research now confirms what common sense has always told us: Happy people live longer, enjoy healthier lives, achieve more success... Look deep to see if you are happy or not and learn what genetics have to do with it.

Date Added: Dec 18, 2007

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Skinny guys must play by different rules and figuring out a workout routine can be a source of confusion and frustration. Here are six reasons skinny guys must focus on strength and a sample training program with notes. Try it now for great success!

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Baby boomers that hit the gym and demand physiques for health, wellness, longevity, and yes, creating and maintaining an attractive body, want to make the most of their time working out. So, how can we maximize our genetics to speed up those results?

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By: Matt Danielsson

Genetics is a popular scapegoat for lazy people. It is very convenient, and there's no one around to prove that this is the sole purpose of fitness limitations for some people! Learn more here ...

Date Added: Nov 7, 2002

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Genetics Articles - Bodybuilding.com

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Abstract

Longevity as a complex life-history trait shares an ontogenetic relationship with other quantitative traits and varies among individuals, families and populations. Heritability estimates of longevity suggest that about a third of the phenotypic variation associated with the trait is attributable to genetic factors, and the rest is influenced by epigenetic and environmental factors. Individuals react differently to the environments that they are a part of, as well as to the environments they construct for their survival and reproduction; the latter phenomenon is known as niche construction. Lifestyle influences longevity at all the stages of development and levels of human diversity. Hence, lifestyle may be viewed as a component of niche construction. Here, we: a) interpret longevity using a combination of genotype-epigenetic-phenotype (GEP) map approach and niche-construction theory, and b) discuss the plausible influence of genetic and epigenetic factors in the distribution and maintenance of longevity among individuals with normal life span on the one hand, and centenarians on the other. Although similar genetic and environmental factors appear to be common to both of these groups, exceptional longevity may be influenced by polymorphisms in specific genes, coupled with superior genomic stability and homeostatic mechanisms, maintained by negative frequency-dependent selection. We suggest that a comparative analysis of longevity between individuals with normal life span and centenarians, along with insights from population ecology and evolutionary biology, would not only advance our knowledge of biological mechanisms underlying human longevity, but also provide deeper insights into extending healthy life span.

Age, I do abhor thee, youth, I do adore thee Shakespeare (1599).

Man possesses the power of modifying, at least to appearance, the laws of nature affecting him, and perhaps causing a progressive movement, tends to approach a happier physical condition Quetelet (1842).

From them (centenarians) we can learn how to create our own Blue Zones and start on the path to living longer, better lives Buettner (2012).

An incessant desire to attain immortality or at the very least greater longevity, and strategies to achieve it, have been recurring themes among the world's mythologies (Witzel, 2013), and continue into our own times (Stambler, 2014). Fundamental insights into birth, growth and death (demographic) processes in human populations are gleaned from the Gompertz-Makeham (Finch, 2007), and Malthusian population laws (Malthus, 1798). Later, Quetelet (1842) systematically investigated the plausible biological and other causes of demographic processes. He questioned, What are laws of human reproduction, growth and physical force the laws of mortality what influence has nature over man, what is the measure of its influence, and of its disturbing forces; what have been their effects for such a period and concluded that, Of all the causes which modify the mortality of man, none exercises a greater influence than age. Research on the evolutionary genetic bases of biological diversity for over a century has shown that longevity, like any other quantitative traits, varies among individuals, and it is influenced by the interaction of both genetic (nature) and numerous environmental factors (nurture; sensu, Galton, 1890). Availability of food resources, improved living conditions and advances in basic and medical sciences have greatly extended the life span globally (Vaupel, 2010), since Quetelet's fundamental work on factors influencing the life span of an average man. In some countries, the modal age of death or the age at which highest mortality occurs in any given population, has steadily increased even in the last fifty years (Horiuchi et al., 2013). Detectable evolutionary changes in modern humans could occur even in such a short span of time (Byars et al., 2010andMilot and Pelletier, 2013), and these changes could have a direct impact on longevity. Despite advances in demography and genetics (Charlesworth, 1980andWachter et al., 2013), Aging remains one of life's great unsolved riddles (Anton, 2013). In view of burgeoning challenges posed by the ever-increasing elderly population, it is critical to understand the components of nature and nurture and the relative magnitude of their contribution to healthy aging.

Comparative analyses of life span across wide-ranging taxa have suggested that longevity has an evolutionary basis (Carey, 2003andWachter et al., 2013). Individuals not only differ in their sensitivity to environmental variations, but also show differential survival and reproduction, in response to such variations, also called natural selection. Environment affects every aspect of viability of individuals from the time of conception to death they are surrounded by it, respond to it, exploit it and also actively construct it (Lewontin, 2000). The latter process has been termed niche construction, which is broadly defined as the process whereby organisms, through their metabolism, their activities and their choices, modify their own and/or each other's niches (Odling-Smee et al., 2003).

An individual or groups of individuals modify their own environment as well as that of others in infinite ways. Some of these modifications, including the ones related to life style could have either proximate or lasting (ultimateevolutionary) effects on health and longevity of specific individuals, families or larger groups. Many aspects of environmental variation and lifestyle changes (LSC) on longevity are inextricably linked, and often difficult to uncouple. Despite their apparent equivalence, LSC represents a volitional behavior on the part of an individual (Egger and Dixon, 2014) and their conscious efforts and choices: education, housing, physical activities, food, drinking and smoking habits, clothing, medical intervention, cultural and religious beliefs, social networks, and so forth. Hence, it is reasonable to suggest that the individual components of the environment and LSC could have either additive or multiplicative or both effects on health and longevity. In an ecological sense, the terms environment and life-style could be equated to niche (Hutchinson, 1957) and niche construction concepts (Lewontin, 2000andOdling-Smee et al., 2013), respectively. From a genetic perspective, gene specific polymorphisms are known to exert differential influence on longevity and its correlated traits. While ecological/environmental factors might have a common influence on all individuals of a group/community, specific aspects of niche construction activities or LSC could exacerbate individual differences. Together these factors would exert synergistic or antagonistic, as well as temporally and spatially heterogeneous effects on longevity at all levels of biological hierarchy: cell, tissues, and individuals within and across generations. These effects could lead to differential viability and reproduction of individuals, which ultimately affect the evolutionary trajectories of individual populations (Odling-Smee et al., 2013andLaland et al., 2014). Here we briefly review the interrelationships among genetic, epigenetic, environment and life style factors influencing life span normal or exceptional.

We have the following objectives: a) to describe the diversity of longevity phenotype among human populations, b) to identify links among genotypic, epigenetic and phenotypic aspects of longevity from the GP map perspective, and c) to discuss modulation of healthy longevity (health span) through lifestyle changes in the context of niche construction, and reaction norm concepts. We conclude that while there are opportunities for augmenting healthy life span, there are biological constraints as well. We extend the genotypephenotype (GP) map metaphor (Lewontin, 1974andHoule et al., 2010) for this purpose, and briefly describe the role of each of the three (genotype-epigenetic-phenotype; G-E-P) spaces as well as discuss their cumulative influence on longevity. We define life span, life expectancy and longevity as species, population and individual specific processes, respectively. Briefly, life span refers to average life expectancy for an individual between birth and death, and hence has a predictive aspect to it. Longevity, on the other hand, is a more elusive concept and is defined as an individual's ability to reach longer life span under ideal or prevailing conditions (Carey, 2003). We use life span and longevity interchangeably.

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Genetics, lifestyle and longevity: Lessons from centenarians

You may get your hair color from your fathers side of the family and your great math skills from your mother. These traits are in the genes, so to speak. Likewise, longevity tends to run in familiesyour genetic make-up plays an important role in how you age. You can see evidence of this genetic connection in families with siblings who live into their 90s or families that have generation after generation of centenarians. These long-lived families are the basis for many genetic studies.

Identifying the genes associated with any trait is difficult. First, just locating the gene requires a detailed understanding of the trait, including knowledge of most, if not all, of the contributing factors and pathways related to that trait. Second, scientists must have clear ways of determining whether the gene suspected to have a relationship with the trait has a direct, indirect, or even no effect on that trait.

Identifying longevity genes is even more complex than determining genes for height or hair color, for example. Scientists do not know all the factors and pathways that contribute to longevity, and measuring a genes effect on long-lived animals, including humans, would literally take a lifetime! Instead, scientists have identified hundreds of genes that affect longevity in short-lived animal models, like worms and flies. Not all of these genes promote long life. Sometimes mutating or eliminating a gene increases lifespan, suggesting that the normal function of the gene limits longevity. Findings in animal models point to places for scientists to look for the genes that may influence longevity in humans.

More here:
Biology of Aging | National Institute on Aging

The LonGenity research study builds upon the Longevity Genes Project, initiated in 1998 at the Albert Einstein College of Medicine by Dr. Nir Barzilai. Dr. Barzilai's early observations of the phenotypes of healthy, vital centenarians led him to ask a series of questions. The project'sprimary focus questioned why some people enjoy extremely long life spans, with physical health and brain function far better than expected in the 9th and 10th decades of life.

In 2006 Dr. Barzilai and his team increased their efforts to conduct a large program, "Roles of genes in exceptional longevity in humans" (LonGenity), funded by the National institute of Aging.

In the LonGenity program, genetic analysis (GWAS and candidate gene approach) is performed in an already established cohort (centenarians, their offspring, and age-match unrelated control to these offspring), and genetic findings are validated in a newly established cohort of offspring of parents with exceptional longevity (OPEL) vs. offspring of parents with usual survival (OPUS).

Over the pastten years Dr. Barzilai's team has assembled and characterized families with exceptional longevity and have identified several biological markers that may explain their longevity. Their hypothesis is that unique genotypes and phenotypes protect against age-related diseases (Figure 1). In order to comply with the steps to prove the causality suggested by the figure 1, novel genetic, epidemiologic, and statistical approaches are used to identify genetic markers in subjects with exceptional longevity, and test the impact of these markers on biological measurements and clinical out comes.The long-term objectives are to identify genes that contribute to exceptional longevity in humans, and assess associations among these genes with age-related diseases and longevity.

The LonGenity research study aims:

To date, a unique cohort of over 500 proband with exceptional longevity (~100 y/o), over 700 of their offspring (ages 60-85), and over 600 unrelated subjects ages 60-95 have been assembled and characterized.

Findings

Results of the research to date have been encouraging and enthusiastically received by the medical research community. Among the findings, the team has learned that longevity is:

Additionally,they have learned that:

Continue reading here:
LonGenity and Longevity Genes Project

Fine-Tuning Your Longevity Genes

By Bryant Villeponteau, Ph.D.

Introduction

The nearly universal human desire to preserve youth can often motivate people to make major lifestyle changes or try the latest wonder supplement. But is it really possible to slow the rate of aging with current knowledge and technology? I argue herein that aging can be significantly slowed by fine tuning your longevity genes. Indeed, scientific research carried out in the last 20 years has shown that lifespan can be readily modulated by a variety of genetic or dietary strategies. In this article, I describe our efforts at Genescient LLC in Irvine, CA, to develop strategies to delay aging and age-related disease. Genescients primary business focus is on the development of pharmaceuticals for age-related diseases, but in conjunction with its spinoff firm Life Code LLC, it has provided testing services for the development of nutraceuticals based on its unique genomics platform. Our findings can be summarized as follows:

What Are the Main Effects of Aging?

Fig. 1: Aging causes an exponential increase in the annual mortality rate.

The actual declines in function with age occur at the cell, organ, and systemic levels, but the impacts of this decline can differ with the individuals genes and environment. The net result of aging is a progressive increase in all-cause mortality and morbidity. In the case of humans, all-cause mortality is known to double every eight years after sexual maturity until it reaches an annual mortality rate plateau of about 50% over 105 years of age.

All grafted data under 110 years are from the Social Security Administration Death Master File, while data on 110 to 119 year olds are from validated human super-centenarians from the website http://www.grg.org.

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Fine-Tuning Your Longevity Genes | Life Code

Is there a maximum biological limit to the human life span of somewhere around 120 years?

Could we live much longer, given the right conditions?

Answers to these and other fundamental questions about aging may now be within reach.

IS THERE AN AGE LIMIT?

One hundred and twenty years, as far as we know, is the longest that anyone has ever lived. A man in Japan, Shirechiyo Izumi, reached the age of 120 years, 237 days in 1986, according to documents that most experts think are authentic. He died after developing pneumonia.

Long lives always make us wonder: What is the secret? Does it lie in the genes? Is it where people live or the way they live -- something they do or do not do? Eat or do not eat? Most of the scientists who study aging, gerontologists, say the secret probably lies in all of the above -- heredity, environment, and lifestyle.

But gerontologists also ask other and more difficult questions. For example, if the 120-year-old had not finally succumbed to illness, could he have lived on and on? Or was he approaching some built-in, biological limit? Is there a maximum human life span beyond which we cannot live no matter how optimal our environment or favorable our genes?

Whether or not there is such a limit, what happens as we age? What are the dynamics of this process and how do they make life spans short, average, or long? Once we understand these dynamics, could they be used to extend everyone's life span to 120 or even, as some scientists speculate, to much greater ages?

And finally for all of us, the most important question: How can insights into longevity be used to fight the diseases and disabilities associated with old age to make sure this period of life is healthy, active, and independent?

In Search of the Secrets of Aging describes what we know so far about the answers to these questions and what we want to know. It gives an overview of research on aging and longevity, showing the major puzzle pieces already in place and, to the extent possible, the shapes of those that are missing.

Originally posted here:
Secrets of Aging, Long Life, longevity Genes

Age (Dordr). 2006 Dec; 28(4): 313332.

1College of Nursing, Okinawa Prefectural University, 1-24-1 Yogi, Naha City, Okinawa Japan 902-0076

2Pacific Health Research Institute, 846 South Hotel Street, Suite 301, Honolulu, HI 96813 USA

3Departments of Geriatric Medicine and Medicine, John A. Burns School of Medicine, University of Hawaii, 1356 Lusitana Street, 7F, Honolulu, HI 96813 USA

4School of Medicine, University of California San Francisco, 74 New Montgomery Street, Suite 600, San Francisco, CA 94105 USA

52200 Post Street, C433, San Francisco, CA 94143-1640 USA

6Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, Japan

Received 2006 Jun 6; Revised 2006 Sep 30; Accepted 2006 Oct 1.

Centenarians represent a rare phenotype appearing in roughly 1020 per 100,000 persons in most industrialized countries but as high as 4050 per 100,000 persons in Okinawa, Japan. Siblings of centenarians in Okinawa have been found to have cumulative survival advantages such that female centenarian siblings have a 2.58-fold likelihood and male siblings a 5.43-fold likelihood (versus their birth cohorts) of reaching the age of 90years. This is indicative of a strong familial component to longevity. Centenarians may live such extraordinarily long lives in large part due to genetic variations that either affect the rate of aging and/or have genes that result in decreased susceptibility to age-associated diseases. Some of the most promising candidate genes appear to be those involved in regulatory pathways such as insulin signaling, immunoinflammatory response, stress resistance or cardiovascular function. Although gene variants with large beneficial effects have been suggested to exist, only APOE, an important regulator of lipoproteins has been consistently associated with a longer human lifespan across numerous populations. As longevity is a very complex trait, several issues challenge our ability to identify its genetic influences, such as control for environmental confounders across time, the lack of precise phenotypes of aging and longevity, statistical power, study design and availability of appropriate study populations. Genetic studies on the Okinawan population suggest that Okinawans are a genetically distinct group that has several characteristics of a founder population, including less genetic diversity, and clustering of specific gene variants, some of which may be related to longevity. Further work on this population and other genetic isolates would be of significant interest to the genetics of human longevity.

Key words: longevity, genetics, centenarians, Okinawa, longevity genes

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Genetic determinants of exceptional human longevity ...

The Institute for Aging Research conducts focused multidisciplinary investigations to unravel essential elements in the biology of aging.

The New York Times and NPR feature Nir Barzilai, M.D., and one of his centenarian study participants in a joint article on aging. (November 19, 2014)

The New York Times profiles Nir Barzilai, M.D. (September 27, 2014)

Wall Street Journal features new research by Nir Barzilai, M.D. that found lower levels of growth hormone are associated with extended lifespan in centenarians. (March 25, 2014)

The Scientist features Ana Maria Cuervo's discovery of how cells selectively break down their waste, and the health consequences that arise when that process malfunctions. (November 1, 2013)

Scientific American interviews Nir Barzilai, M.D., about latest research advances for slowing or delaying the aging process in humans. Dr. Barzilai, who conducts longevity research with centenarians, notes his superagers tend to have a significant delay in the onset of age-related diseases and stay healthier longer. Dr. Barzilai is the Ingeborg and Ira Leon Rennert Chair of Aging Research and director of the Institute for Aging Research at Einstein and attending physician at Montefiore Medical Center.

Nature features Nir Barzilai, M.D., and his proposed TAME study, which will investigate if the widely used diabetes drug metformin can delay aging. Dr. Barzilai notes that he and his colleagues are not seeking the fountain of youth, but rather an effective means to extend the number of healthy years an individual has, or healthspan. Dr. Barzilai is the Ingeborg and Ira Leon Rennert Chair of Aging Research and director of the Institute for Aging Research at Einstein and attending physician at Montefiore Medical Center.

The Scientist interviews Nir Barzilai, M.D., and Evris Gavathiotis, Ph.D., about their success in pursuing private funding in the face of federal funding cuts. Drs. Barzilai and Gavathiotis share how they identified and pursued alternative funding sources and how it has helped advance their research. Dr. Barzilai is the Ingeborg and Ira Leon Rennert Chair of Aging Research and director of the Institute for Aging Research at Einstein and attending physician at Montefiore Medical Center. Dr. Gavathiotis is assistant professor of biochemistry and of medicine.

The New York Timesreferences Einsteins centenarian studies and Nir Barzilai, M.D., in an obituary on 109-year old Irving Kahn. Kahn, considered the oldest active Wall Street investor before his death, was a participant in Dr. Barzilais studies at EinsteinsInstitute of Aging Research. He was also profiled as part of EinsteinsLongevity Genes Project video series. Dr. Barzilai is the Ingeborg and Ira Leon Rennert Chair of Aging Research and director of the Institute for Aging Research at Einstein and attending physician at Montefiore Medical Center.

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Overview | Institute for Aging Research | Albert Einstein ...

Annual herd turnover rates and reported reasons for culling may be misleading, and the timing of culling during the lactation can be a more useful indicator of potential management problems on a given farm. Conformation traits are often used to select for improved cow longevity, but these traits account for only a modest proportion of differences in cow survival. Significant genetic variation exists between sires in the length of productive life of their daughters, as well as susceptibility to specific health disorders. Genetic improvement of cow survival should focus on direct measures of longevity, fertility, and health.

Dairy cow survival is influenced by many factors. Non-genetic factors include stall size, bedding type, degree of overcrowding, heat abatement devices, nutrition, veterinary care, herd expansion plans, milk quota restrictions, and availability and affordability of replacement heifers. As shown below, genetic improvement of longevity involves breeding animals that can produce a live calf without assistance; cycle normally, show visible heat, and conceive when inseminated; maintain adequate body condition and resist metabolic disorders; avoid udder injuries and fight off infection by mastitis pathogens; walk and stand comfortably without frequent hoof trimming, and efficiently produce milk of desirable composition. Many cows fail to complete these tasks and leave the herd prematurely. In some cases, the cow is genetically flawed, while in other cases her environment is lacking. Significant genetic variation exists between sire families for longevity, fertility, calving performance, and disease resistance. Therefore, we can improve longevity directly by selecting families that resist culling, or we can improve longevity indirectly by selecting families that excel for each of its component traits.

Please check this link first if you are interested in organic or specialty dairy production

Much negative attention has been given to the annual turnover or replacement rates on commercial dairy farms. However, the overall replacement rate for a given herd doesnt provide enough information to indicate whether or not a problem exists; one needs to know which cows left the herd, as well as the reasons for and timing of their removal. Suppose that 35% of the milking cows in each of two dairies were replaced last year. In one herd, the majority of these were low-producing, older animals that were culled late in lactation and subsequently replaced by younger, genetically superior heifers grown from within the operation. In the other herd, the majority were young, high-producing cows that were culled or died early in lactation due to calving problems, mastitis, lameness, ketosis, and other metabolic disorders, and the owner was forced to buy springing heifers from a cattle dealer at the prevailing market price. Thus, even though the replacement rates on these farms are identical, ones interpretation of each herd's management success is vastly different. Replacement rates can also be misleading in herds that have an excess of replacement heifers. Suppose one herd sells its extra animals as springing heifers prior to first calving, while another herd calves all of its heifers and culls stringently for low production within the milking herd. Both may be successful in terms of managing the health, fertility, and productivity of their cattle, but the former will have a substantially lower annual replacement rate. In general, herds with lower replacement or turnover rates tend to be more successful in terms of cow comfort, health, and productivity. However, replacement rates can be misleading, and more detailed information about the reasons for culling and the timing of culling is needed. Furthermore, herd turnover rates are influenced heavily by external factors, such as expansion plans and replacement heifer prices.

Dairy producers routinely report reasons for disposal as part of the national milk recording program. Animals can be recorded as died, sold for dairy, or sold for beef, with the latter category broken down into low production, mastitis, infertility, and so on. These descriptive reasons for disposal can be useful when studying the general demographics of a national dairy herd. For example, one might use such data to conclude that mastitis and infertility are the most common causes of culling on most dairy farms. However, reported reasons for disposal can be misleading when one attempts to compare the management level of various dairy farms, or when one attempts to draw conclusions about the genetic merit of certain animals or sire families. Many animals are culled for multiple offenses. For example, a cow might have a difficult calving, followed by a case of ketosis, and a displaced abomasum. She may then fail to breed back in a timely manner and be culled from the herd when her daily milk production drops below a profitable level. The farmer might code her as sold for low production, sold for infertility, or sold due to disease. Thus, the reported reason for disposal is often a vague indicator of the actual problem. Furthermore, inconsistencies may exist between reported reasons for disposal and the actual health and reproductive history of the culled animals.

Stewart (Steve Stewart, Univ. of Minnesota, 2002, unpublished) proposed the idea of using the timing of culling within the lactation as an indirect indicator of the reason for disposal. He constructed a graph showing the proportion of total culled animals that were removed within certain time periods during the lactation. An example of this type of graph is shown below, where the percentage of culled cows that left during each 3-week period from calving to 440 d postpartum is shown for 59,390 cows that calved in 2001-2003 and were subsequently culled from 151 herds that participate in the Alta Genetics (Watertown, WI) Advantage Progeny Testing Program. One can hypothesize that cows that were culled between 0 and 62 d postpartum may have left due to calving problems or early lactation metabolic disorders, while cows that were culled between 63 and 293 d postpartum may have left due to mastitis or lameness, and cows that were culled after 294 d postpartum may have left due to infertility. Exceptions to the rule exist, as a cow that is culled today may actually reflect the outcome of a do not breed decision that occurred many months earlier. Nonetheless, an analysis of the timing of culling events within a dairy herd may provide a more objective description of management on a given farm than one can obtain by inspecting the overall turnover rate or reported reasons for disposal. Furthermore, genetic evaluation of dairy sires based on the proportion of daughters that were culled during each period of the lactation may provide a useful indicator of differences in susceptibility to various diseases or disorders. For example, one could compute sire predicted transmitting abilities for early lactation survival, and this might identify bulls whose daughters avoid calving complications and resist early postpartum metabolic disorders.

Initial attempts to improve dairy cow longevity through artificial selection began in the 1970s and early 1980s when breed associations and AI studs first developed linear type appraisal programs. For the next two decades, type and longevity were considered as synonymous. Bulls that sired daughters with high, wide rear udders, strong median suspensory ligaments, well-attached fore udders, and correct teat placement were considered to transmit superior longevity. Likewise, bulls that sired daughters with strong pasterns, a steep foot angle, and correct set to the hock were expected to improve longevity.

Numerous studies have addressed the genetic relationships between linear type traits and longevity (e.g., Caraviello et al., 2004a; Sewalem et al, 2004; Short and Lawlor, 1992). Early studies relied on the estimation of genetic correlations between longevity and linear type traits, and these studies typically invoked a 60-, 72-, or 84-month opportunity period for longevity. However, these studies suffered from two major limitations. First, the use of genetic correlation parameters to assess trait-longevity relationships limited these studies to measurement of linear relationships only. Few traits have a strictly linear relationship with longevity, and the role of traits with intermediate optima or traits that offer diminishing returns as scores increase cannot be evaluated properly using genetic correlations. Second, the use of a long opportunity period, to allow each cow to fully express her genetic potential for longevity, resulted in a tremendous time lag between the birth of animals in the study group and eventual publication of results. For example, the youngest cows in the Short and Lawlor (1992) study were born in 1982, so more than a decade of additional genetic and management improvements occurred prior to publication of results of the study. The use of survival analysis methodology in more recent studies (e.g., Caraviello et al., 2004b) alleviated several of the aforementioned limitations. In many of these studies, linear type scores were grouped into categories, and no restrictions were placed on the form of the trait-longevity relationship. Furthermore, because survival analysis allows proper modeling of censored records from animals that are still alive (Ducrocq, 1994), these studies used much more timely data than previous studies that invoked a long opportunity period. Results indicated that many type traits, such as rear leg set, rump angle, or dairy form, have intermediate optima, while many others, such as udder support, teat placement, or foot angle, seem to display a pattern of diminishing returns. More importantly, these studies demonstrated that udder depth, fore udder attachment, rear udder attachment, and udder support were of primary importance with respect to longevity, while rear leg set and foot angle were of secondary importance, and stature had no importance. Despite the importance of physical conformation, a significant proportion of the genetic variation in longevity remained unexplained by existing type or production traits well into the 1990s. Numerous examples were noted of bulls that transmitted outstanding production and type to their daughters but whose daughters nonetheless tended to leave the herd prematurely. Thus, type traits can be used as an indirect indicator of the expected longevity of a bull's daughters, and actual culling and fertility data are needed to explain the rest of the story.

In 1994, the USDA Animal Improvement Programs Laboratory (Beltsville, MD) introduced national genetic evaluations for length of productive life (PL), which was measured as the total number of months in milk from first calving until 84 mo of age, with a limit of 10 mo per lactation (VanRaden and Klaaskate, 1993). Because the vast majority of cows are culled by 84 mo of age, this seems to provide a reasonable opportunity period. In fact, the additional gain in accuracy that could be achieved by waiting for a few, highly selected daughters to complete 8, 10, or 12 yr of PL would be negligible. Because the starting point of the opportunity period (date of first calving) can vary, it is possible that this definition of PL may favor animals that calve at a young age. However, the phenotypic variation in age at first calving on most commercial dairies is rather limited. The limit of 10 mo of PL per lactation was applied for two reasons: because it seemed desirable to penalize cows that have a long dry period and an extended calving interval and because test-day production data beyond 305 d postpartum were unavailable historically. However, this restriction may have some unintended consequences, in terms of the genetic relationships between PL and other traits in the breeding goal. Tsuruta et al. (2005) showed that the genetic correlation between milk yield and PL changed from -0.11 with a 305 d limit, to +0.08 with a 500 d limit, and to +0.14 with a 999 d limit. Corresponding genetic correlations between days open and PL were -0.62, -0.36, and -0.27 for per lactation PL limits of 305 d, 500 d, and 999 d, respectively, while genetic correlations with dairy form were -0.25, -0.12, and -0.08, respectively. An extension of the current 305 d limit to a value that is more closely aligned with the management of modern commercial dairies, such as 365 d or 400 d, has been discussed. An additional argument for extending, or even removing, a limit on PL credits per lactation is that national dairy sire evaluations for daughter pregnancy rate (DPR) are now routinely available, and indirect selection for fertility using PL information is no longer necessary. An important aspect of current national genetic evaluations for PL is that records of cows that are still alive can be extended or projected to obtain an estimate of the total months in milk that such animals will accumulate by culling or 84 mo of age (VanRaden and Klaaskate, 1993). Thus, the 84-mo opportunity period does not cause a major delay or time lag in computing sire PTA for PL. On the other hand, the accuracy of such projections is low much lower than the accuracy of projected 305 d milk production records based on the first two or three test-day yields.

The primary concern with regard to genetic evaluation of PL is the substantial period of time required to obtain complete culling data for daughters of a given bull. Because a short generation interval is desirable in genetic selection programs, AI studs and pedigree breeders like to make sire selection decisions as quickly as possible. However, when a recently tested sire is being considered as a sire of sons or as an embryo transfer sire, most of his daughters are still alive. Therefore, reliability of PL evaluations is often low at the most critical points in life. This can lead to errors in selection decisions, particularly for bulls whose daughters fail to follow a typical maturity pattern. If a particular bull's daughters mature more or less gracefully than daughters of an average bull, his PTA can change significantly over time. Weigel et al. (1998) developed a procedure by which correlated traits, such as type, production, and somatic cell score, can be used to compute an indirect prediction of a bulls PTA for PL. The indirect prediction for a given bull can then be combined with his direct prediction, which is based on actual culling data, using weights that depend on the REL of direct and indirect predictions. The combined PTA will have higher REL than either the direct or indirect prediction, especially early in life. Although the combined PL predictions tend to be more accurate than direct predictions for the majority of sires, there are exceptions. The most disturbing cases are bulls whose daughters appear promising in first lactation but mature less gracefully than daughters of an average bull. These bulls tend to have a high indirect prediction early in life, but their combined PTA tends to decrease over time, as daughters mature and get culled from the herd more rapidly than anticipated.

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Genetic Improvement of Dairy Cow Longevity - eXtension

A handful of genes that control the body's defenses during hard times can also dramatically improve health and prolong life in diverse organisms. Understanding how they work may reveal the keys to extending human life span while banishing diseases of old age

By David A. Sinclair and Lenny Guarente

You can assume quite a bit about the state of a used car just from its mileage and model year. The wear and tear of heavy driving and the passage of time will have taken an inevitable toll. The same appears to be true of aging in people, but the analogy is flawed because of a crucial difference between inanimate machines and living creatures: deterioration is not inexorable in biological systems, which can respond to their environments and use their own energy to defend and repair themselves.

At one time, scientists believed aging to be not just deterioration but an active continuation of an organism's genetically programmed development. Once an individual achieved maturity, "aging genes" began to direct its progress toward the grave. This idea has been discredited, and conventional wisdom now holds that aging really is just wearing out over time because the body's normal maintenance and repair mechanisms simply wane. Evolutionary natural selection, the logic goes, has no reason to keep them working once an organism has passed its reproductive age.

Yet we and other researchers have found that a family of genes involved in an organism's ability to withstand a stressful environment, such as excessive heat or scarcity of food or water, have the power to keep its natural defense and repair activities going strong regardless of age. By optimizing the body's functioning for survival, these genes maximize the individual's chances of getting through the crisis. And if they remain activated long enough, they can also dramatically enhance the organism's health and extend its life span. In essence, they represent the opposite of aging genes--longevity genes.

We began investigating this idea nearly 15 years ago by imagining that evolution would have favored a universal regulatory system to coordinate this well-known response to environmental stress. If we could identify the gene or genes that serve as its master controllers and thereby act as master regulators of an organism's life span, these natural defense mechanisms might be turned into weapons against the diseases and decline that are now apparently synonymous with human aging.

Many recently discovered genes, known by such cryptic names as daf-2, pit-1, amp-1, clk-1 and p66Shc, have been found to affect stress resistance and life span in laboratory organisms, suggesting that they could be part of a fundamental mechanism for surviving adversity. But our own two laboratories have focused on a gene called SIR2, variants of which are present in all organisms studied so far, from yeast to humans. Extra copies of the gene increase longevity in creatures as diverse as yeast, roundworms and fruit flies, and we are working to determine whether it does the same for larger animals, such as mice.

As one of the first longevity genes to have been identified, SIR2 is the best characterized, so we will focus here on its workings. They illustrate how a genetically regulated survival mechanism can extend life and improve health, and growing evidence suggests that SIR2 may be the key regulator of that mechanism.

One of us (Guarente) began by screening yeast colonies for unusually long-lived cells in the hope of finding genes responsible for their longevity. This screen yielded a single mutation in a gene called SIR4, which encodes part of a complex of proteins containing the Sir2 enzyme. The mutation in SIR4 caused the Sir2 protein to gather at the most highly repetitive region of the yeast genome, a stretch containing the genes that encode the protein factories of the cell, known as ribosomal DNA (rDNA). More than 100 of these rDNA repeats exist in the average yeast cell's genome, and they are difficult to maintain in a stable state. Repetitive sequences are prone to "recombining" with one another, a process that in humans can lead to numerous illnesses, such as cancer and Huntington's disease. Our yeast findings suggested that aging in mother cells was caused by some form of rDNA instability that was mitigated by the Sir proteins.

In fact, we found a surprising kind of rDNA instability. After dividing several times, yeast mother cells spin off extra copies of the rDNA as circular rings that pop out of the genome. These extrachromosomal rDNA circles (ERCs) are copied along with the mother cell's chromosomes prior to cell division but remain in the mother cell's nucleus afterward. Thus, a mother cell accumulates an ever increasing number of circles that eventually spell her doom, possibly because copying the ERCs consumes so many resources that she can no longer manage to replicate her own genome.

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Longevity genes - Supercentenarian