Genetic Mechanisms of Aging

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. 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, and many people over age 60 suffer from chronic illnesses or disabilities. 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. 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.” It is generally assumed that accumulated damage to a variety of cellular systems is the underlying cause of aging. 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 function ; (2) the insulin/IGF-1 signaling (IIS) hypothesis suggesting that extended life span is associated with reduced IIS signaling ; (3) the somatic mutation/repair mechanisms focusing on the cellular capacity to respond to damage to cellular components, including DNA, proteins, and organelles ; (4) the immune system plays a central role in the process of aging ; (5) the telomere hypothesis of cell senescence, involving the loss of telomeric DNA and ultimately chromosomal instability ; and (6) inherited mutations associated with risk for common chronic and degenerative disorders. 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, 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, 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. An early report examining the integrity of mtDNA found accumulated mtDNA damage more pronounced in senescent rats compared with young animals. Other reports followed, including age-associated decreases in the respiratory chain capacity in various human tissues. 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. Furthermore, mtDNA haplotypes are associated with longevity in humans. In sum, this mitochondrial genome–ROS production theory of aging is mechanistically sound and appealing.

Deletions are the most commonly reported mtDNA mutations accumulating in aging tissues, and evidence for their role in aging is considered supporting. In order to solidify the importance of mtDNA damage in aging, Trifunovic et al 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. 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. 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. 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. This was subsequently supported by evidence from a number of other cell types. 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 complex 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. 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. 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. Furthermore, the intracellular distribution of mitochondria could play a role in the manifestation of the effects of mtDNA mutations.

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. Moreover, as the role of mitochondria in the response to caloric restriction is gaining relevance, available data are contradictory and not easily reconciled. 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.