Human longevity: genetics or lifestyle?

It takes two to tango

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

Giuseppe Passarino et al., Immunity & Ageing, 2016

Translated by Evgenia Ryabtseva

Healthy aging and longevity of people are determined by a successful combination of genetic and non-genetic factors. Family studies have shown that the variability of human life expectancy by about 25% depends on genetic factors. The search for the genetic and molecular basis of aging has led to the identification of genes correlating with the maintenance of the cell's vital activity and its basic metabolism as the main genetic factors influencing the individual variability of the aging phenotype. In addition, studies on the effects of a low-calorie diet and genes associated with nutrient-recording signaling pathways have shown that a low-calorie diet and/or genetically efficient nutrient metabolism can adjust life expectancy by ensuring effective maintenance of cells and the body. Recent epigenetic studies have demonstrated that epigenetic modifications modulated by both the genetic profile and lifestyle are very sensitive to the aging process and can both act as biomarkers of the quality of aging and influence the speed and quality of aging.

In general, the results of modern research indicate that interventions that change the interaction between the genetic profile and the environment are necessary to determine an individual's chances of longevity.

The number of studies devoted to the study of aging and, in particular, the search for factors determining successful aging and active longevity has been continuously increasing over the past decades, including due to the growing burden on the social and medical spheres, correlated with the gradually increasing life expectancy of people in developed countries and, accordingly, the growth of the elderly population. One of the main issues in this area is the correlation between the genetic profile and lifestyle in determining a person's chance of postponing aging (possibly without age-related diseases and disability) and longevity. The results obtained by biogerontologists over the years, illuminating most of the biological and biochemical mechanisms involved in the aging process, provided a better understanding of this correlation. This has led to the emergence of complex important strategies aimed at developing possible interventions aimed at improving lifestyle in order to increase the chances of longevity by modulating the basic molecular mechanisms of aging.

Genetics of aging

Until the 1990s, the hypothesis that aging is inevitable and is not regulated by genetic factors was widespread. From this point of view, the idea was important, according to which aging occurs at the end of reproduction, when there is no longer not only the need, but also the possibility for selection acting on genes expressed in the later stages of life [1].

The first researcher who devoted his work to studying the genetics of aging and longevity was Tom Johnson, who worked with populations of C.elegans roundworms, in which he could separate long-lived individuals from short-lived ones. Based on the results of the study of hybrid organisms obtained by crossing different lines of worms, he found that the life expectancy is 20-50% due to heredity [2, 3]. After that, he began to study the characteristics of various mutants and, together with M. Klass, identified several mutants with obviously increased life expectancy. Further studies showed that most of the long-lived mutants had age1 gene mutations [4]. It turned out that this gene encodes a catalytic subunit of the enzyme phosphatidylinositol-3-kinase class I (PI3K).

Johnson's research has clearly demonstrated that genetic variability can indeed have an impact on life expectancy. This stimulated the conduct of many studies on model organisms, the purpose of which was to decipher various biochemical mechanisms capable of influencing life expectancy, as well as the identification of genes encoding proteins involved in these mechanisms. Yeast, C.elegans roundworms, fruit flies, fruit flies and mice were mainly used as models (the latest version of the list of such genes can be found on the GenAge website http://genomics.senescence.info/genes/models.html ). Most of these genes are related to maintaining cell integrity (especially DNA integrity). However, in C.elegans, some of the main genes modulating life expectancy (daf2, daf16) are associated with the ability to enter the dower state [5, 6] – this is a state of rest or "sleep" (usually characteristic of nutrient deficiency conditions) with minimal energy costs, leading to the termination of the reproductive process and allowing the body to live longer "waiting" for the appearance of nutrients. Based on this, it is logical to assume that longevity can be achieved by effectively maintaining the vital activity of the cell, as well as by redistributing resources from the reproduction process to the maintenance of vital activity, which is consistent with earlier results, according to which a low-calorie diet can increase life expectancy. After describing these genes in C.elegans, it was found that in mice, the orthologue of the daf16 (FOXO) gene can also influence life expectancy. In mammals, FOXO correlates with the insulin/insulin-like growth factor-1 signaling axis stimulated by the availability of nutrients and, through FOXO, activates the process of protein synthesis [7-11].

It should be noted that, according to the assumptions of some authors, these life-span-modulating molecular mechanisms may be due to the pleiotropic effect of genes that appeared during evolution to solve various problems (such as genes of the signaling pathway mediated by insulin-like growth factor-1, which appeared during evolution as a mechanism responding to the availability/absence of nutrients), however, ultimately able to have an impact on life expectancy. Others suggested that some genes could have appeared in the course of evolution to implement the aging program and exclude "immortality", since it would prevent the continuous replacement of old individuals with new, younger representatives of the species [12, 13].

It is obvious that the focus of research devoted to the study of the genetic foundations of longevity has inevitably shifted to humans and to elucidate the ability of genetic variants common in human populations to influence inter-individual differences in life expectancy, as well as to identify a potential correlation between genes that increase the life expectancy of model organisms and human life expectancy.

As for the first question (do common genetic variants affect life expectancy and, in particular, do they determine longevity?), it was studied using two approaches. The first consisted in reconstructing the family tree of long-lived people [14, 15] and comparing the survival curves of its members with the survival curves of contingents of people born in the same year in the same regions. This approach demonstrated that the siblings of long-lived people had a clear advantage in terms of survival (at any age) relative to the general population. The second approach, using intra-family controls, was started by Montesanto et al. to distinguish between genetic and "family" effects [15], it consisted in comparing the survival function of long-lived brothers with the corresponding parameters for their brothers-in-law, that is, men married to their sisters. It was assumed that these men lived in conditions similar to those of the long-lived brothers. Using this approach, it was found that the brothers of centenarians did not fully share their survival advantages with their sisters' husbands, despite the fact that they lived in similar conditions for most of their lives. These results indicated that in addition to the family environment, genetic factors influence survival and, accordingly, life expectancy. An interesting fact is that in this study, the survival curve for the sisters of centenarians did not differ from the curve of centenarians for the wives of their brothers, which indicates a more pronounced role of the genetic component in the survival of men than in the survival of women. The genetic component of human life expectancy was also analyzed by comparing the age at the time of death of identical and fraternal twins. Based on the results obtained, it was found that the variability of human longevity by about 25% is due to genetic factors, as well as the fact that this component is more pronounced in the later stages of life and is more important for men than for women [16-18].

In parallel with the work described above, many researchers have been searching for genetic variants responsible for modulating human longevity. Such work was carried out mainly using the "case-control" method, which consisted in comparing the frequency of occurrence of certain polymorphisms in long-lived people and younger members of the control group living in the same geographical area. The logical rationale for this research design is that as the population ages, survival-friendly alleles in long-lived people will occur with a higher frequency, while unfavorable alleles will be eliminated [19-21]. The candidate genes analyzed using this approach were either genes involved in the development of age-related diseases (such as the apolipoprotein E (APOE) gene involved in the formation of predisposition to the development of Alzheimer's disease and other age-related pathologies), or genes involved in signaling pathways associated with longevity during studies on model organisms (insulin-like growth factor-1 (IGF-1), FOXO, sirtuins) [22-25]. Such studies have indeed led to the discovery of numerous polymorphic genes, the variability of which has an impact on longevity. However, as it turned out, each of these polymorphisms explained only a small part of the variability of longevity. Indeed, recently conducted high-performance genome-wide analyses have revealed many genes that have a positive relationship with longevity, but only very few of them have passed multiple tests to verify statistical significance and reproduced their results in various studies conducted for different populations [26-29]. Stratification of populations and inadequate sample sizes proved to be the most plausible explanations for this [30]. The introduction of innovative research design and the development of new statistical and computational tools for the efficient processing of genetic data obtained using high-performance DNA technologies will help to better understand the complex genetic architecture underlying human longevity [31, 32].

A new approach to the study of genetic data was proposed by Raule et al. [33], who analyzed the complete mitochondrial DNA sequences of long-lived people from different regions of Europe. The availability of complete sequences at the disposal of the authors made it possible for the first time to evaluate the cumulative (cumulative) effects of specific concomitant mutations of mitochondrial DNA (mtDNA), including those that individually have little or very little effect. The results of the analysis showed that the presence of single mutations in the mtDNA complex I can be useful from the point of view of longevity, whereas the presence of concomitant mutations on two complexes I and III or I and V at once can reduce a person's chances of longevity. Earlier analyses of single mutations on complex I (specific mutations or mutations defining groups of haplotypes) have yielded contradictory results, in some cases demonstrating an association with longevity, and in others – its absence. Probably positive results were obtained for populations in which mutations of complex I were not associated with mutations of complexes III or V, whereas negative results were obtained for populations with a high frequency of mtDNA haplotypes carrying mutations of complex I in association with mutations of complexes III and V. The results obtained using this approach confirmed that most of the genetic variants have a very limited effect on longevity, and that only their cumulative effect can form the basis of stable significant manifestations. In addition, they indicate that the limit of the possibility of the previously used methods of analysis was the identification of individual mutations, and not cumulative effects. On the other hand, it is very difficult to talk about using this approach, which was used to study mitochondrial DNA, to genomic DNA, except for the analysis of small fractions (or specific regions containing genes involved in the corresponding signaling pathways).

In general, the results of studies of genetic associations indicate that in the case of humans, mutations of genes associated with maintaining cell viability and its basic metabolism are also fundamental in modulating life expectancy. Indeed, it has been found that genes involved in repairing DNA damage [34], maintaining telomere length [35-37], heat shock reaction [38, 39], as well as regulating free radical levels [33, 40], contribute to longevity or, in the case of reduced functionality, accelerated entry into the phase of physiological aging (cellular aging) and subsequent aging of the body. In addition, as shown by the results of studies in mice, signaling pathways involved in the registration of nutrients and regulation of transcription, such as the insulin-like growth factor-1/insulin axis [41] and the target protein rapamycin (TOR), [42] participate in the modulation of human longevity. According to the results of parallel work, especially clinical studies, in addition to these genes involved in the maintenance of cell activity/metabolism and physiological aging, genes involved in important organizational processes can make a great contribution to aging and longevity. For example, it has been found that genes involved in the metabolism of lipoproteins (especially apolipoprotein E), homeostasis of the cardiovascular system, immunity and inflammation play an important role in aging, the development of age-related diseases and longevity of the body [43-46].

Human longevity and lifestyle

In Western countries, life expectancy at birth has been increasing for almost the entire last millennium due to continuous improvements in the quality of medical care, living conditions (especially access to clean, safe water and food), as well as food. For example, in Italy, life expectancy increased from 29 years in 1861 to 82 years in 2011 (changes in this indicator for women and men are shown in table 1). Similarly, the indicators of exceptional longevity have increased over the years. The number of centenarians who have passed the 100-year mark (also in Italy) has increased significantly from 165 in 1951 to more than 15,000 in 2011. These results were mainly achieved by reducing the incidence of infectious diseases, which, in turn, greatly reduced both infant mortality and mortality among adults. In fact, in 2011, less than 10% of deaths occurred in people under 60 years of age, whereas in 1872, 1901 and 1951, the mortality rate of people of the same age was 74%, 56% and 25%, respectively. However, over the past decades, the continuous increase in life expectancy has been mainly due to the improvement in the quality of medical care for age-related diseases, especially cardiovascular diseases and cancer, which has provided an increase in life expectancy by 5 years over the past two decades and by 2 years over the past ten years (data from the websites www.mortality.org and www.istat.it ).

These data clearly demonstrate that factors of living conditions have a pronounced impact on human life expectancy and longevity. However, the increase in life expectancy observed in recent decades is not accompanied by a similar increase in the period of healthy life expectancy. And indeed, in most cases this increase in life expectancy is due to the transfer of age-related diseases to a chronic state. This has led biogerontologists to search for interventions, possibly using the knowledge gained from studying the genetic and biomolecular foundations of aging, aimed at increasing not only life expectancy, but also the duration of a healthy life. In fact, model organisms with life-extending mutations maintain good health even in old age. This indicates the possibility of increasing the duration of a healthy life by the influence (stimulation or suppression of activity) of genes involved in the mechanisms of prolongation of life in both model organisms and humans [47]. In support of this hypothesis, evidence suggests that the gene expression profile of mice on a low-calorie diet living longer and showing a significant delay in the development of the aging phenotype compared to animals with unlimited access to food in old age significantly differs from the gene expression profile of mice of the same age for a number of genes correlated with an increase in the duration of life, including for genes associated with DNA damage repair, stress response, immune response, etc. [48, 49] Thus, a low-calorie diet can trigger a molecular genetic reaction that delays aging and the development of age-related phenotypes. This has prompted researchers to search for drugs or interventions that can affect these mechanisms without the side effects of a low-calorie diet. The most important interventions considered in this context include a low-protein diet and the use of drugs that affect different genes of the insulin-like growth factor-1 axis or the FOXO/TOR signaling pathway [47]. In addition, such studies have allowed us to revise earlier data collected in regions famous for exceptional longevity of residents (such as Okinawa, Sardinia and Calabria). Such regions are characterized by a traditional low-protein diet, one of the variants of which is the "Mediterranean diet" [50-53]. In such cases, living conditions, in the form of a traditional diet, provided stimulation of molecular mechanisms that contribute to an increase in life expectancy.

Among several changes occurring during the aging process, the field of epigenomics has attracted the interest of many scientists over the past 10 years. This is mainly due to the fact that epigenetic modifications, at least partially summarizing the interaction between the individual genetic profile and lifestyle features, theoretically should explain part of the currently incomprehensible predisposition to complex diseases (problems of so-called lost heritability).

Starting with the groundbreaking observations according to which epigenetic modifications have an impact not only on the aging process, but also on its quality (successful aging) [54], hundreds of regions scattered throughout the genome have been identified during full-epigenomic studies of associations, the levels of methylation of which differ for the oldest and younger people. In particular, Horwat and co-authors based on the methylation levels of 353 CpG islands formulated a mathematical model with a number of important qualities, the so-called epigenetic clock [55]. Firstly, it made it possible to predict the chronological age of a person based on the levels of methylation of the genomes of several cells and tissues of his body. Secondly, it is one of the most accurate biomarkers of age (including exceeding the estimated values obtained using telomere length values). Thirdly, the results obtained using data on the levels of methylation of the genomes of blood cells and the brain of people with Down syndrome showed that this syndrome accelerates the aging process [56]. Fourth, after making adjustments to traditional risk factors, it made it possible to predict mortality from all causes [57]. And finally, when using a number of super-centenarian tissues to assess the biological age, she demonstrated that in such exceptional people, the brain and muscle tissue are the youngest tissues [58].

However, even if the causal relationship between the methylation process and aging is still unclear, the scope of potential application of this discovery is very wide, ranging from detailed monitoring of changes occurring with age in individual body systems or organs (muscle tissue, brain, etc.), and ending with the tasks of criminology. For this and several other reasons, future achievements in this field may help to deepen knowledge about the complex physiology of aging, life expectancy and age-related diseases.

Conclusion

In general, despite the fact that general variability explains only 25% of the variability in human life expectancy, knowledge of the genetic basis of longevity modulation can provide valuable tips on lifestyle adjustments to achieve longevity and increase life expectancy. That is, only some people will be able to enjoy longevity thanks to a successful combination of polymorphisms that will allow them to have an effective metabolism or an effective response to various forms of stress. Most of the rest of the people will be able to achieve the same effect by influencing the same mechanisms by following an appropriate lifestyle or performing certain interventions. In this context, the importance of epigenetic factors, not only as biomarkers of aging, but also as targets for interventions, will definitely increase in the near future.

For a list of references, see the original article.

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27.05.2016