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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

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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 ...

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)

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5 Ways to Prevent a First Heart Attack - Verywell

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Genetic Anti-Aging and Health: Creating REAL Results by ...

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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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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 ...

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Genetics Articles - Bodybuilding.com

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Resveratrol By RevGenetics Resveratrol Benefits, Anti ...

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

Read the original:
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

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In July last year I wrote about some fairly glaring flaws in a paper published in Science on the genetics of extreme longevity. At the time, potential problems with the paper had been flagged in an excellent Newsweek piece by Mary Carmichael.

Today, after a year in advance online limbo without ever progressing to the print edition of the journal, and a formal Expression of Concern last November, the paper was fully retracted. Theres solid coverage of the announcement at the Boston Globe (including quotes from my Genomes Unzipped colleague Jeff Barrett), Nature, and of course the superb Retraction Watch.

Heres the retraction notice in full:

After online publication of our Report Genetic signatures of exceptional longevity in humans (1), we discovered that technical errors in the Illumina 610 array and an inadequate quality control protocol introduced false-positive single-nucleotide polymorphisms (SNPs) in our findings. An independent laboratory subsequently performed stringent quality control measures, ambiguous SNPs were then removed, and resultant genotype data were validated using an independent platform. We then reanalyzed the reduced data set using the same methodology as in the published paper. We feel the main scientific findings remain supported by the available data: (i) A model consisting of multiple specific SNPs accurately differentiates between centenarians and controls; (ii) genetic profiles cluster into specific signatures; and (iii) signatures are associated with ages of onset of specific age-related diseases and subjects with the oldest ages. However, the specific details of the new analysis change substantially from those originally published online to the point of becoming a new report. Therefore, we retract the original manuscript and will pursue alternative publication of the new findings.

In a statement quoted over at Retraction Watch, the journal makes it more clear how the retraction decision was actually reached:

Sebastiani and colleagues submitted the corrected data to Science in December 2010, where the work underwent careful peer-review. Although the authors remain confident about their findings, Science has concluded on the basis of peer-review that a paper built on the corrected data would not meet the journals standards for genome-wide association studies. One such standard, for example, is the inclusion of a reliable replication sample that shows comparable results to those in the initial experiments.

The authors have therefore agreed to retract their paper.

In other words, the authors were still willing to stand by their results, but the journal wasnt.

Questions remain about how the study managed to pass through peer review in the first place virtually every complex trait geneticist I spoke to was immediately, massively skeptical about the articles findings from the moment of publication but it appears that Science has conducted a thorough investigation of the authors amended manuscript and made an appropriate decision. It will be intriguing to see if, when and in what form the studys authors manage to republish their results.

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Longevity genetics study retracted from Science | WIRED

Genetics of Human Longevity: New Ideas & Findings

Natalia Gavrilova

Center on Aging, NORC at the University of Chicago

(Abstract of presentation at the International Conference on Longevity, Sydney, Australia, March 5-7, 2004)

In contrast to the remarkable progress in the genetics of yeast and nematode aging, little is known about genes that control human longevity. What is behind the records of extreme human longevity: just lucky chance, favorable environment, or 'good' genes? How to resolve the apparent controversy between strong familial clustering of human longevity, and poor resemblance in lifespan among blood relatives?

We applied methods of genetic epidemiology and survival analysis to family-linked data on human lifespan. Special efforts were undertaken to collect detailed and reliable human genealogies an important data source for genetic studies of human longevity. We found that the dependence of offspring lifespan on parental lifespan is essentially non-linear, with very weak resemblance before parental lifespan of 80 years and very steep offspring-parent dependence (high narrow-sense heritability) for longer lived parents. There is no correlation between lifespan of spouses, who share familial environment. These observations suggest that chances to survive beyond age 80 are significantly influenced by genetic factors rather than shared familial environment. These findings explain the existing longevity paradox: although the heritability estimates for lifespan are rather low, the exceptional longevity has a strong familial association.

We also tested the prediction of mutation theory of aging that accumulation of mutations in parental germ cells may affect progeny lifespan when progeny was conceived to older parents. We found that daughters conceived to older fathers live shorter lives, while sons are not affected. Maternal age effects on lifespan of adult progeny are negligible compared to effects of paternal age, which is consistent with the notion of higher rates of DNA copy-errors in paternal germ cells caused by more intensive cell divisions during spermatogenesis.

Genealogical data also are useful for testing the prediction of the disposable soma theory that human longevity comes with the cost of impaired reproductive success. We found that in contrast to previous reports by other authors, woman's exceptional longevity is not associated with infertility. Thus, the concept of heavy infertility cost for human longevity is not supported by data, when these data are carefully cross-checked, cleaned and reanalyzed. These results demonstrate the importance of high quality genealogical data for genetic studies of human longevity.

Relevant Publications:

Gavrilov, L.A., Gavrilova, N.S. Early-life factors modulating lifespan. In: Rattan, S.I.S. (Ed.).Modulating Aging and Longevity. Kluwer Academic Publishers, Dordrecht, The Netherlands, 2003, 27-50.

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Genetics of Human Longevity - Longevity Science

Chromosomes and DNA. adam.about.net

Updated December 30, 2014.

What is a Telomere?:

A chromosome is a long strand of DNA. At the end of a chromosome is a telomere, which acts like a bookend. Telomeres keep chomosomes protected and prevent them from fusing into rings or binding with other DNA. Telomeres play an important role in cell division.

What Happens When a Cell Divides?:

Each time a cell divides, the DNA unwraps and the information in the DNA is copied. The process does not copy all of the DNA information - the telomeres are not copied.

When the cell is finished dividing, the DNA comes back together. The telomeres lose a little bit of length each time this happens.

Why Do They Get Shorter?:

When a cell divides and copies DNA, the strands of DNA get snipped to enable the copying process. The places that are snipped are the telomeres. Since the telomeres do not contain any important information, more important parts of the DNA are protected. The telomeres get shorter each time a cell divides, like a pencil eraser gets shorter each time it's used.

Can Telomeres Become Too Short?:

The rest is here:
Telomeres and Aging - Understanding Cellular Aging

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With several companies on the verge of mass-marketing genetic tests that claim to read agings cellular clock, some researchers say the science isnt yet ready for prime-time use.

The tests measure telomeres, or protein sheaths that prevent the tips of chromosomes from fraying. As time passes, they grow shorter, a process hastened by stress, environmental insult and disease. If they get too short, cell breakdown follows. A large body of research links telomere deterioration to deteriorating health.

That makes telomeres an alluring target for quantifying the ravages of aging, which have proved surprisingly difficult to measure. But the clinical use of telomeres has yet to be determined.

Aging is extremely complex. Its going to involve many behavioral and genetic factors, said Boston University gerontologist Thomas Perls, who runs the worlds largest study of centenarian health. Its going to be unwise to try and pin it down on one particular marker. There are going to be many different factors.

Telomere tests came to public notice this week after an article in The Independent described a test being developed by Life Length, a Madrid startup company. In the article, University of Texas Southwestern geneticist and Life Length consultant Jerry Shay extolled the tests potential.

When youre looking at a whole bunch of people, you conclude that shorter telomeres are bad. But that doesnt mean you can take an individual and tell them their risk.

Telomere length is actually a pretty good representation of your biological age, he said. People might say If I know Im going to die in 10 years, Ill spend all my money now. Or, If Im going to live for 40 more years Ill be more conservative in my lifestyle.'

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To Measure Longevity, Common Sense Trumps Genetic Test

More than 400 mutations were found in the healthy white blood cells of a 115-year-old woman, according to a new study that may advance what is known about limits of the human life span.

Genetic mutations have been linked to diseases such as cancer, but these findings suggest that mutations in white blood cells are largely harmless over a lifetime, the researchers said.

Blood is continually replenished by hematopoietic (meaning "to make blood") stem cells that are inside the bone marrow and divide to produce different types of blood cells.

Cell division can lead to genetic mutations and hundreds of mutations have been found in patients with blood cancers. However, little was known about white blood cells and mutations.

The woman in the study - whose name was not revealed - was the oldest person in the world when she died in 2005. She is thought to be the oldest person ever to donate her body to science. The hundreds of mutations identified in her white blood cells appeared to be tolerated by the body and did not cause disease.

The researchers also found possible new insight into the limits of human longevity, according to the authors of the study published online April 23 in the journal Genome Research.

"To our great surprise we found that, at the time of her death, the peripheral blood was derived from only two active hematopoietic stem cells (in contrast to an estimated 1,300 simultaneously active stem cells), which were related to each other," lead author Dr. Henne Holstege said in a journal news release.

The researchers also found that the woman's white blood cells' telomeres were extremely short. Telomeres, which are at the ends of chromosomes and protect them from damage, get a bit shorter each time a cell divides.

"Because these blood cells had extremely short telomeres, we speculate that most hematopoietic stem cells may have died from 'stem cell exhaustion,' reaching the upper limit of stem cell divisions," Holstege said.

Further research is needed to learn whether such stem cell exhaustion is a cause of death in extremely old people.

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Scientists seek genetic clues to longevity from 115-year ...

Updated May 21, 2014.

What It Is:

The genetic theory of aging believes that lifespan is largely determined by the genes we inherit. According to the theory, our potential age is primarily determined at the moment of conception.

The Evidence Behind the Theory:

There is some evidence to support this theory. People with parents who have lived long lives are more likely to live long themselves (though this could be partially explained by learned behaviors, such as food preferences).

Also, identical twins (who have the exact same genes) have closer lifespans than siblings.

How Genes Impact Lifespan:

Some genes are beneficial and enhance longevity -- a gene that helps a person metabolize cholesterol would reduce a person's risk of heart disease, for example. But some genes are harmful, like those that increase the risk cancer. Some gene mutations are inherited, too, and may shorten lifespan. (Mutations also can happen after birth, since exposure to toxins, free radicals and radiation can cause gene changes.)

The Bottom Line:

It is estimated that genes can explain a maximum of 35 percent of lifespan. The other determinants are your behaviors, exposures, and just plain luck. So don't think that you are doomed just because your family members tend to die young -- and also don't think that you can ignore your health if your family members tend to live long.

See more here:
Genetics and Aging - The Genetic Theory of Aging