Genetic and epigenetic regulation of aging

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Many age-associated conditions, such as the decrease in regenerative capacity of tissues, appear to be determined by a decline in the function of specific somatic stem cells. Although it is obvious that the genotype determines the average lifespan of different species, the variation in lifespan of individuals within a species seems to be more affected by the accumulation over time of molecular errors that compromise adult stem cell function. These molecular alterations can occur at both the genetic and epigenetic levels and depend on hereditary, environmental, and stochastic factors. This complex multifactorial mixture determines characteristics, such as longevity and a healthy life, that are central concerns of human existence.

Introduction

The process of aging in humans, understood as the loss of corporal functions accompanied by a general degeneration of cells and tissues, most likely arises from the progressive decay of adult stem cells’ potential to maintain correct tissular homeostasis [1, 2]. The factors involved in the process and the reasons for its occurrence have been a matter of debate for decades. It is indisputable that the genotype determines the variation in average maximum lifespan between species: for example, some organisms, such as the nematode C. elegans, live less than one month while others, such as giant tortoises, can live for hundreds of years [3]. However, the variation in lifespan among individuals of the same species seems to be more strongly affected by the accumulation over time of molecular errors that compromise adult stem cell function than by specific genetic programs [2, 4]. These molecular alterations can occur at both the genetic and epigenetic levels and depend on the genotype (intrinsic factors), the environment (extrinsic factors), and stochastic (undetermined) factors. Thus, species-specific genotypes may determine the general program of ontogenic development and the maximum lifespan of the species while the intraspecies-specific peculiarities of the process of aging are determined by a complex multifactorial combination of genetic, environmental, and stochastic factors, whose relative contributions are yet to be fully elucidated (Figure 1). In our species, this combination governs characteristics, such as longevity and healthy life that are central to human existence.

This article reviews the types of genetic and epigenetic alterations that accumulate over time, their potential to affect somatic stem cell function, and the hereditary, environmental, and stochastic factors involved in their establishment.

Section snippets

The role of genetic factors in aging

The role of genetic factors in aging has many facets. One concerns the fact that specific combinations of genes (species-specific genotypes) determine the general order of magnitude of the lifespan. This is demonstrated by the wide variation in the average lifespan of different species and is also consistent with the dramatic changes in lifespan observed as a result of the alteration of a single gene, as occurs in human progeroid syndromes [5]. A second facet concerns the impact of hereditary

The role of epigenetics in aging

The term epigenetics, which was originally coined to define how genotypes give rise to phenotypes through programed changes during development [27••], today refers to the study of stable genetic modifications that result in changes in gene expression and function without a corresponding alteration in DNA sequence. The best-known epigenetic modifications are DNA methylation and histone post-transcriptional modifications, including methylation, acetylation, ubiquitination, and phosphorylation [28

Concluding remarks and perspectives

In conclusion, the aging phenotype primarily results from the decline of the capacity of adult stem cells to regenerate tissues and organs. The great variation in lifespan within isogenic individuals of the same species suggests that this decline is affected more by the accumulation over time of molecular errors that compromise adult stem cell function than by specific genetic programs. These molecular alterations occur at both the genetic and epigenetic levels and depend on hereditary,

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

MFF is funded by the Health Department of the Spanish Government (PI061267) and the Spanish National Research Council (Ref. 200820I172).

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