Genetic and epigenetic regulation of aging
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).
References (56)
- et al.
Epigenetics and aging: the targets and the marks
Trends Genet
(2007) Understanding the odd science of aging
Cell
(2005)- et al.
Age to survive: DNA damage and aging
Trends Genet
(2008) - et al.
Mitochondrial DNA mutations and aging: devils in the details?
Trends Genet
(2009) - et al.
The p66shc adaptor protein controls oxidative stress response and life span in mammals
Nature
(1999) - et al.
Effects of telomerase and telomere length on epidermal stem cell behavior
Science
(2005) - et al.
Translating the histone code
Science
(2001) - et al.
Aging results in hypermethylation of ribosomal DNA in sperm and liver of male rats
Proc Natl Acad Sci U S A
(2003) - et al.
Production of different phenotypes from the same genotype in the same environment by developmental variation
J Exp Biol
(2008) - et al.
How stem cells age and why this makes us grow old
Nat Rev Mol Cell Biol
(2007)
Time of our lives. What controls the length of life?
EMBO Rep
Genetic determinants of human health span and life span: progress and new opportunities
PLoS Genet
Genetic influence on human lifespan and longevity
Hum Genet
Molecular bases of progeroid syndromes
Hum Mol Genet
Werner and Hutchinson–Gilford progeria syndromes: mechanistic basis of human progeroid diseases
Nat Rev Mol Cell Biol
Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson–Gilford progeria syndrome mutation
Proc Natl Acad Sci U S A
Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice
Nat Genet
A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria
Science
Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging
Nat Med
Adiponectin levels and genotype: a potential regulator of life span in humans
J Gerontol A Biol Sci Med Sci
A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4
Proc Natl Acad Sci U S A
Chromosome 4q25, microsomal transfer protein gene, and human longevity: novel data and a meta-analysis of association studies
J Gerontol A Biol Sci Med Sci
Genetic mapping in human disease
Science
Human models of aging and longevity
Expert Opin Biol Ther
Cross-talk between aging and cancer: the epigenetic language
Ann N Y Acad Sci
Hematopoietic dysfunction in a mouse model for Fanconi anemia group D1
Mol Ther
Cellular senescence in cancer and aging
Cell
High-throughput telomere length quantification by FISH and its application to human population studies
Proc Natl Acad Sci U S A
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