Genetic Mechanisms of Aging

Chao-Qiang Lai, Laurence D. Parnell, José M. Ordovás

Introduction

Our society is experiencing unprecedented demographic changes where improvements in health care and living conditions together with decreased fertility rates have contributed to the aging of the population and a severe demographic redistribution.¹ Over the last 50 years, the ratio of people aged 60 years and over to children younger than 15 increased by about half, from 24 per hundred in 1950 to 33 per hundred in 2000. Worldwide by the year 2050, there will be 101 people 60 years and older for every 100 children 0 to 14 years old,² and many people over age 60 suffer from chronic illnesses or disabilities.³ Therefore, to better understand the mechanisms of aging and the genetic and environmental factors that modulate the rate of aging, it is essential to cope with the impact of these demographic changes.⁴ Aging can be defined as “a progressive, generalized impairment of function, resulting in an increased vulnerability to environmental challenge and a growing risk of disease and death.”⁵ It is generally assumed that accumulated damage to a variety of cellular systems is the underlying cause of aging.⁵ To date, a large proportion of aging research has focused on individual age-related disorders compromising adult life expectancy and healthy aging, including cardiovascular disease (heart disease, hypertension), cerebrovascular diseases (stroke), cancer, chronic respiratory disease, diabetes, mental disorders, oral disease, and osteoarthritis and other bone/joint disorders. Environmental factors, such as diet, physical activity, smoking, and sunlight exposure, exert a direct impact on these disorders, whereas significant genetic components make separate contributions. Although individual genetic factors could be small differences in DNA sequences—single nucleotide polymorphisms or small insertions/deletions—in both the nuclear and mitochondrial genomes, the overall genetic contribution to aging processes is polygenic and complex.

The complexity of aging is reflected in that numerous models have been proposed to explain why and how organisms age and yet they address the problem only to a limited extent. The models that are more widely accepted include: (1) the oxidative stress theory implicating declines in mitochondrial function⁶; (2) the insulin/IGF-1 signaling (IIS) hypothesis suggesting that extended life span is associated with reduced IIS signaling⁷; (3) the somatic mutation/repair mechanisms focusing on the cellular capacity to respond to damage to cellular components, including DNA, proteins, and organelles⁸; (4) the immune system plays a central role in the process of aging⁹; (5) the telomere hypothesis of cell senescence, involving the loss of telomeric DNA and ultimately chromosomal instability¹⁰; and (6) inherited mutations associated with risk for common chronic and degenerative disorders.¹¹^,¹² In this work we will elaborate on the genetic component of each of these six hypotheses and the need for a more integrative approach to aging research.

Mitochondrial Genetics, Oxidative Stress, and Aging

The central role of mitochondria in aging, initially outlined by Harman,¹³ proposed that aging, and associated chronic degenerative diseases, could be attributed to the deleterious effects of reactive oxygen species (ROS) on cell components. As the major site of ROS production, the mitochondrion is itself a prime target for oxidative damage. Moreover, this is the only organelle in animal cells with its own genome, (mtDNA), which is mostly unprotected, closely localized to the respiratory chain, and subject to irreversible damage by ROS. Specifically, accumulation of mtDNA somatic mutations, shown to occur with age,¹⁴ often map within genes encoding 13 protein subunits of the electron transport chain (ETC) or 24 RNA components vital to mitochondrial protein synthesis. Not surprisingly, this mtDNA damage has been associated with deleterious functional alterations in the activity of ETC complexes. These mutations, whether single point mutations or deletions, have been shown in many studies to be associated with aging and with multiple chronic and degenerative disorders.¹⁵ An early report examining the integrity of mtDNA found accumulated mtDNA damage more pronounced in senescent rats compared with young animals.¹⁶ Other reports followed, including age-associated decreases in the respiratory chain capacity in various human tissues.¹⁷ Hypotheses put forward stated that acquired mutations in mtDNA increase with time and segregate in mitotic tissues, eventually causing decline of respiratory chain function leading to age-associated degenerative disease and aging.¹⁷ Furthermore, mtDNA haplotypes are associated with longevity in humans.¹⁸^,¹⁹ In sum, this mitochondrial genome–ROS production theory of aging is mechanistically sound and appealing.²⁰

Deletions are the most commonly reported mtDNA mutations accumulating in aging tissues, and evidence for their role in aging is considered supporting.²¹ In order to solidify the importance of mtDNA damage in aging, Trifunovic et al²² developed a mouse model that indicated a causative link between mtDNA mutations and aging phenotypes in mammals. This “mtDNA mutator” mouse model was engineered with a defect in the proofreading function of mitochondrial DNA polymerase (Polg), leading to the progressive, random accumulation of mtDNA mutations during mitochondrial biogenesis. As mtDNA proofreading in these mice is efficiently curtailed, a phenotype develops with a threefold to fivefold increase in the levels of point mutations.²² However, the abnormally higher rate of mutation took place during early embryonic stages, and mtDNA mutations continued to accumulate at a lower, near normal rate during subsequent life stages.²³ Although these mice display a completely normal phenotype at birth and in early adolescence, they subsequently acquire many features of premature aging, such as weight loss, reduced subcutaneous fat, alopecia, kyphosis, osteoporosis, anemia, reduced fertility, heart disease, sarcopenia, progressive hearing loss, and decreased spontaneous activity.²² Such results confirm that mtDNA point mutations can cause aging phenotypes if present at high enough levels, but alone do not prove that the lower levels measured in normal aging are sufficient to cause aging phenotypes. Hence, attention turned to the focal distribution of mtDNA mutations rather than the overall amount as key in disrupting the efficiency of the respiratory chain and thus driving the observed aging phenotypes. To prove this hypothesis, Müller-Höcker examined hearts from individuals of different ages and reported focal respiratory chain deficiencies in a subset of cardiomyocytes in an age-dependent manner.²⁴ This was subsequently supported by evidence from a number of other cell types.²⁵^–²⁷ In sum, intracellular mosaicism, resulting from uneven distribution of acquired mtDNA mutations, can cause respiratory chain deficiency and lead to tissue dysfunction in the presence of low overall levels of mtDNA mutations.

The mitochondrial hypothesis of aging is conceptually straightforward, but in reality is much more complex²⁸ because a minimal threshold level of a pathogenic mtDNA mutation must be present in a cell to cause respiratory chain deficiency, and this threshold may vary between experimental models.²⁹ With 100 to 10,000 mtDNA copies per cell, mtDNAs that are mutated and normal at a given position coexist within a cell, tissue, or organ—a condition termed heteroplasmy. Different types of heteroplasmic mtDNA mutations have different thresholds for induction of respiratory chain dysfunction.¹⁷ Moreover, subjects carrying heteroplasmic mtDNA mutations often display varying levels of mutated mtDNA in different organs and even in different cells of a single organ.¹⁷ Furthermore, the intracellular distribution of mitochondria could play a role in the manifestation of the effects of mtDNA mutations.³⁰

Although significant advances in our understanding of the role of mitochondria in aging have been made, it is likely that current theories will be revised as the link between mtDNA mutations and ROS production is more deeply probed.³¹ Moreover, as the role of mitochondria in the response to caloric restriction is gaining relevance, available data are contradictory and not easily reconciled.³² Thus research efforts will continue to describe the role of the mitochondrion in influencing the mechanisms of aging, but several boundaries should be heeded: (1) the difference in complexity between humans and model organisms at genetic, cellular, and organ levels; (2) the particular life span of each species, especially as medicine has allowed humans to live beyond a “normal” age of death; (3) the genetics of inbred animals often used in experiments contradicts humans who are highly outbred; and (4) the environmental conditions in which animals (highly standardized) and humans (quite different for anthropologic and cultural reasons) live.³³

Chromosomal Gene Mutations and Aging

Genetic factors associated with human longevity and healthy aging remain largely unknown. Heritability estimates of longevity derived from twin registries and large population-based samples suggest a significant but modest genetic contribution to human life span of about 15% to 30%.³⁴ However, genetic influences on life span may be greater as an individual ages.³⁵ Moreover, the reported magnitude of the genetic contribution to other important aspects of aging such as healthy physical aging (wellness), physical performance, cognitive function, and bone aging are much larger.³⁴ Both exceptional longevity and a healthy aging phenotype have been linked to the same region on chromosome 4,³⁶^,³⁷ suggesting that although longevity per se and healthy aging are different phenotypes, they may share some common genetic pathways.

A number of potential candidate genes in a variety of biologic pathways have been associated with longevity in model organisms. Most of these genes have human orthologs and thus have potential to yield insights into human longevity.³⁸

First, the most prominent hypothesis of aging states that mutants with decreased signaling through the insulin/IGF-1 signaling (IIS) pathway have extended life span. This pathway is evolutionarily conserved from nematodes to humans.³⁹ Thus genes of this pathway are promising candidate genes for influencing human longevity and healthy aging. Several studies have reported the association between genetic variants at IGF1R and PI3KCB and reduction of insulin-IGF-1 activation and longevity.⁴⁰^,⁴¹ The finding that a nonsynonymous mutation in IGF1R was found to be overrepresented in centenarians of shorter stature when compared with controls⁴² supports a role for the IIS pathway in life-span extension in humans, thus extending observations in model organisms.

Second, macromolecule repair mechanisms regulate the process of aging.⁶ Dysfunctional systems for damage repair to cellular constituents, such as DNA, proteins, and organelles, could curtail life span. These repair mechanisms are evolutionarily conserved across species.⁴³ Many studies support the detrimental effects of defective repair on reduced life span. Examples are human premature aging patients with mutations in a RecQ helicase, a crucial enzyme responsible for DNA strand break repair.⁴⁴ Variation at this gene has shown association with cardiovascular diseases.⁴⁵ However, few studies have demonstrated that an enhanced repair ability increases life span.⁴⁶ In addition, the altered protein/waste accumulation in the process of aging could aggravate cellular damage.¹⁰ Thus dysfunction in clearance of cellular waste, which is also called autophagy, would accelerate aging. Downregulation of autophagy gene expression, such as Atg7 and Atg12, has shortened the life span of both wild type and daf-2 mutant Caenorhabditis elegans.⁴⁷

Third, the immune system plays a central role in the process of aging.⁹ Although inflammation is an essential defense of immune systems, chronic inflammation often leads to premature aging and mortality.⁴⁸ One key player of inflammation is the cytokine interleukin 6 (IL6). IL6 overexpression has been linked to many age-related that such as rheumatoid arthritis, osteoporosis, Alzheimer disease, cardiovascular diseases, and type 2 diabetes.⁴⁹^,⁵⁰ Human studies have also demonstrated that IL6 genetic variation is associated with longevity.⁵¹^,⁵²

Finally, cardiovascular disease is the major cause of morbidity and mortality in industrialized countries and thus a major obstacle to healthy aging and longevity. Much attention has been placed on genes encoding proteins functioning in lipid metabolism. Plasma lipid levels are highly dependent on age, gender, nutritional status, and other behavioral factors. It is therefore difficult, at least in cross-sectional studies, to determine to what extent a particular lipoprotein phenotype is causally associated with aging. One way to circumvent this issue is to rely on long-term prospective studies or to perform family-based studies.¹¹ Well-designed case-control genetic studies may also be advantageous because identification of particular variants associated with longevity may provide some hints to the biologic pathways leading to exceptional longevity. To that end, a large number of allelic variants in genes encoding apolipoproteins (APOE, APOB, APOC1, APOC2, APOC3, APOA1, and APOA5), transfer proteins (microsomal transfer protein [MTP], cholesteryl ester transfer protein [CETP]), proteins associated with HDL particles (PON1), and transcription factors involved in lipid metabolism (peroxisome proliferator-activated receptor gamma [PPARG]) have been examined in elderly populations. Similar to many other aspects of lipoprotein metabolism and cardiovascular disease risk, the most explored locus in terms of associations with longevity has been that of the apolipoprotein E (APOE) gene. Since the initial observation by Davignon et al,⁵³ reports from different parts of the world have observed a higher frequency of the APOE4 allele in middle-aged subjects compared with older subjects (octogenarians, nonagenarians, and centenarians), concluding that the presence of the APOE4 allele was associated with decreased life span.⁵⁴

To summarize, data accumulated so far illustrate that a variety of genes are involved in several mechanisms of aging, age-related diseases, and to a certain extent with longevity. Although thus far tenuous, there are a number of clues indicating that there is crosstalk between genes involved in longevity and those involved in age-related diseases that could be involved in longevity beyond effects on healthy aging.

Genetics is a valuable tool to expand our understanding of the molecular basis of aging. However, most studies published so far have been limited by design (e.g., cross-sectional study, small sample size, limited SNP coverage of a small number of candidate genes, interethnic differences) and so results have been inconsistent.⁵⁵ Most recently, genomewide association studies (GWAS) offer a more comprehensive and untargeted approach to detect genes with modest phenotypic effects that underlie common complex conditions.⁵⁶ Some notable findings are emerging from GWAS with a focus on aging-related phenotypes.³⁴^,⁵⁷^,⁵⁸ However, to benefit fully from the contribution of genetics, large prospective studies need to be undertaken and fully supported by extensive genotyping and analytical capacities to collect adequate phenotype data. Even more important is the urgent need for a reliable intermediate phenotype for aging, both for genetic studies and for therapeutic interventions.⁵⁷

Telomeres and Aging

Telomeres are repetitive DNA sequences that are wrapped in specific protein complexes and located at the ends of linear chromosomes. Telomeres distinguish natural chromosome ends from DNA double-stranded breaks and thus promote genome stability.⁵⁹ Although traditionally considered as silent structural genomic regions, recent data suggest that telomeres are transcribed into RNA molecules, which remain associated with telomeric chromatin, suggesting RNA-mediated mechanisms in organizing telomere architecture.⁶⁰

Telomere length has been proposed as a potentially reliable marker of biologic age, shorter telomeres reflecting more advanced age. Thus telomeres fit within mechanisms explaining the Hayflick limit⁶¹ because they shorten progressively with each cell division. When a critical telomere length is reached, cells undergo senescence and subsequent apoptosis. Initial telomere length is mainly determined by genetic factors.⁶²^,⁶³ Although telomere shortening may be a normal biologic occurrence with each cell division, exposure to harmful environmental factors may affect its rate, accelerating telomere shortening.⁶⁴ To counter telomere shortening, telomerase, a cellular reverse transcriptase, promotes maintenance of telomere ends in human stem cells, reproductive cells, and cancer cells by adding TTAGGG repeats onto the telomeres. Moreover, recent studies suggest the existence of chromosome-specific mechanisms of telomere length regulation determining a telomere length profile, which is inherited and upheld throughout life.⁶⁵ Telomerases also may be involved in several essential cell signaling pathways without apparent involvement of well-established functions in telomere maintenance.⁶⁶ However, most normal human cells do not express telomerase and thus each time a cell divides some telomeric sequences are lost. When telomeres in a subset of cells become short (unprotected), cells enter an irreversible growth arrest state called replicative senescence.⁶⁷ The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders, including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer.⁶⁸ In addition to this manifestation in rare genetic disorders, short telomeres have been reported in the general population for several common chronic diseases, such as cardiovascular diseases,⁶⁹^,⁷⁰ hypertension,⁷¹ diabetes,⁷² and dementia.⁷³ With respect to cancer,⁷⁴ dysfunctional telomeres activate the oncoprotein p53 (TP53) to initiate cellular senescence or apoptosis to suppress tumorigenesis. However, in the absence of p53, telomere dysfunction is an important mechanism to generate chromosomal instability commonly found in human carcinomas.⁷⁵ Telomerase is expressed in the majority of human cancers, making it an attractive therapeutic target. Emerging antitelomerase therapies, currently in clinical trials, might prove useful against some human cancers.⁷⁶

Based on current evidence, telomere shortening clearly accompanies human aging, and premature aging syndromes often are associated with short telomeres. These two observations are central to the hypothesis that telomere length directly influences longevity. If true, genetically determined mechanisms of telomere length homeostasis should significantly contribute to variations of longevity in the human population. Unraveling cause versus consequence of telomere shortening observed in the course of many aging-associated disorders is not an easy task. In addition, it remains unclear whether the biomarker value in a particular disease depends on shorter telomere length at birth or rather if it is merely a reflection of an accelerated telomere attrition during lifetime, or a combination of both. Although the importance of telomere attrition is supported by cross-sectional evidence associating shorter telomeres with oxidative stress and inflammation, longitudinal studies are required to accurately assess telomere attrition and its presumed link with accelerated aging.⁷⁷

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