StemCell Therapy

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

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