The accumulation of somatic damage is now considered a main cause of the aging process in species varying from nematodes and insects to mice and humans.
Among the various sources of somatic damage, reactive oxygen species (ROS), the natural by-products of oxidative energy metabolism, are often considered as the ultimate cause of aging.
However, free radicals also participate in physiological processes that benefit fitness, such as growth factor signal transduction.
Thus, optimal energy production must be balanced against the damaging effects of ROS.
This trade-off is highlighted by several recent reports on mouse mutants with extended life-span.
Inactivation of certain gene, which controls stress-induced ROS and apoptosis, leads to significant life-span extension together with increased resistance to ROS.
Similarly, the inactivation of the gene for insulin-like growth factor I, important for growth and metabolism, significantly lengthens the life-span of mice and increases resistance to ROS.
Interestingly, this possible trade-off between growth and reproduction and somatic maintenance is in keeping with suggestion that caloric restriction may extend life-span by attenuating the oxidative stress caused by normal metabolism.
In general, there is a price to be paid for such unnaturally high somatic maintenance, and that price is reduced reproductive success.
This is not necessarily apparent in laboratory settings but can be revealed by simulating more "natural" environments.
What is the route from ROS to the adverse effects associated with aging?
Among myriad possibilities, alterations in the genome have long been considered critically important.
Recent results obtained with mouse models that show accelerated rather than retarded aging as a consequence of defects in genome maintenance systems support this view and are beginning to shed light on the question how we age.
One of the cellular targets of ROS is DNA.
More than 100 different types of oxidative DNA lesions have been described, ranging from base modification to single- and double-strand DNA breaks and interstrand cross-links.
These lesions disrupt vital processes such as transcription and replication, which may cause cell death or growth arrest or may induce mutations that lead to cancer.
To cope with DNA damage, organisms evolved an intricate network of DNA damage repair pathways, each focusing on a different class of lesions.
Excision systems deal with lesions that affect only one DNA strand, which permits excision of the lesion and subsequent use on the intact complementary strand to fill the gap.
Base excision repair and nucleotide excision repair remove subtle and more helix-distorting types of damage, respectively.
They operate genome-wide and are important for preventing mutations.
Transcription-coupled repair, on the other hand, eliminates lesions that actually block the transcription machinery, thus helping to repair those genes that are actually used by the cell.
Transcription-coupled repair system uses many components of nucleotide excision repair.
Together base excision repair, transcription-coupled repair and (to a lesser extent) nucleotide excision repair are critically important for repairing ROS-induced base damage and single-strand breaks.
ROS can also induce DNA double strand breaks, which are repaired by homologous recombination, when another DNA copy is available (after replication) or by nonhomologous end joining.
Finally, interstrand cross-links, another double-strand lesion that can be induced by ROS, are eliminated in a poorly understood fashion probably involving homologous recombination and some nucleotide excision repair components.
DNA lesions also cause problems during replication, a time of great vulnerability for the cell.
Some of the damage incurred during replication is bypassed by a special class of translesion polymerases at the expense of a higher risk of mutations.
Recombination systems as well as other proteins also play a role in coping with DNA lesions during replication.
Do any of these genome maintenance systems prevent age-related phenotypes by ameliorating or repairing DNA damage caused by oxidative metabolism?
Natural human mutants provided the first evidence that they do, but these mutants had been discovered long before the discovery of DNA repair.
In humans, several heritable mutations accelerate the onset of multiple aging phenotypes (Table 1).
Disorders caused by these mutations are termed segmental progeroid syndromes, because they accelerate some but not all signs of normal aging.
||Incidence (per live birth)
||Genome maintainance defect
||Alopecia, sclerosis, wrinkling, soft tissue, cachexia, arteriosclerosis, diminished fat.
||Alopecia, osteoporosis, malignancies, arteriosclerosis, diabetes, cataracts, telangiectasia, skin atrophy, graying of hair.
||DNA helicase (Rec-Q like), exonuclease
||Alopecia, malignancies, poikiloderma, cataracts, osteoporosis, graying of hair.
||DNA helicase (Rec-Q like)
||Thin hair, cachexia, retinal degeneration, hearing loss, neurodegeneration (cerebral ataxia), cataracts
||Transcription coupled DNA repair
||Cachexia, osteoporosis, cataracts, fragile hair, neurodegeneration (cerebral ataxia)
||DNA repair, basal transcription
||Skin atrophy/scelrosis, telangiectasia, immunodeficiencies, malignancies, graying of hair, poikiloderma, neurodegeneration (cerebral ataxia)
||DNA damage signaling protein kinase
||Cataracts, graying of hair, alopecia, diminished subcutaneous fat, vision loss, neurodegeneration (Alzheimers-like), thyroid dysfunction
Table 1. Most commonly described human segmental progeroid syndromes.
The most prominent of the currently known premature aging syndromes were described a century ago, about the time DNA was first described by Miesher in his first attempts to identify the chemical makeup of cell nuclei.
By now it is known that many of the heritable mutations giving rise to the symptoms of accelerated aging in these patients partially or wholly inactivate proteins that sense or repair DNA damage.
This finding suggests that failure to maintain genomic integrity underlies at least some aging phenotypes.
Although not all heritable defects in DNA repair display symptoms of accelerated aging, it is striking that so many progeroid disorders are linked to defects in genome maintenance.
The mouse could prove to be a powerful model for understanding the importance of genome maintenance in human longevity.
The genomes of mice and humans are similar and genome maintenance mechanisms are generally highly conserved.
Mouse mutants defective in genome maintenance are now available and like their human counterparts, many display segmental progeria.
To understand the basis of accelerated aging that occurs in human and mouse mutants, it is important to consider the molecular and cellular changes that can result from defective genome maintenance.
As shown in Fig. 1, a direct consequence of unpaired DNA damage is transcription interference, which is very likely responsible for the symptoms trichothiodystrophy and Cockayne syndrome.
A general decline in transcription occurs in a variety of organs and tissues with increasing age.
Figure 1. Possible molecular and cellular endpoints of aging as driven by DNA damage from energy metabolism. This concept is based on the trade-off between somatic maintenance and growth and reproduction.
Moreover, an indirect endpoint of DNA damage is mutation, as a consequence of error-prone repair or misreplication.
The accumulation of mutations in organs and tissues during aging could cause the well-known increase in cancer and possibly lead to a variety of functional decrements, especially when large genome rearrangements are involved.
Apart from the immediate molecular consequences of transcription interference and mutation accumulation, DNA damage may also elicit cellular responses.
In mammals, two major cellular responses to genotoxic stress are apoptosis (programmed cell death) and cellular senescence.
Both of these responses protect against cancer by eliminating severely damaged cells that are at risk for malignant transformation.
However, while offering such a benefit at younger age, increased loss of functional cells in organs and tissues may explain some prominent symptoms of aging, such as neurodegenerative diseases, loss of immune function and heart and kidney functional decline.
Of these two cellular endpoints, cellular senescence is least understood.
Cellular senescence was first described as replicative senescence, which refers to the limited proliferative potential and eventual growth arrest shown by all normal human and animal cells in culture.
The process is often considered as a model for cellular dysfunction in vivo.
The condition of high oxygen tension in the culture medium greatly shortens the replicative life-span, particularly of mouse cells, suggesting that the senescence response to ROS may underlie differences in aging rate between mice and human.
Replicative senescence in humans is caused by telomere shortening, which results in excessive chromosomal instability.
However, senescence in culture also results from treatment with DNA-damaging agents, such as ionizing radiation, mitomycin C and oxidative stress, as well as through activated oncogenes.
Thus, DNA damage can elicit a transient growth arrest, apoptosis or cellular senescence, all designed to prevent cancer, but apoptosis and cellular senescence may also contribute to aging.
Cells from humans or mice with defects in genome maintenance often undergo accelerated senescence, including cells with genetic alterations.
Because senescent cells arrest growth without dying and acquire altered function that can in principle disrupt tissue homeostasis, it has been proposed that their accumulation contributes to certain aging phenotypes, including cancer.
Thus, the direct cause of premature aging seen in repair-deficient mice and humans may not be DNA damage, somatic mutation or interference with transcription or replication, but rather a cellular response.
If defects in genome maintenance lead to accelerated aging in humans and mice, is it possible that normal aging is caused in part by inadequately repaired DNA damage?
Genome maintenance is necessarily imperfect, because organisms are not designed to last forever and genetic changes are needed for natural selection.
Mutations in one or a few of a possibly hundreds of genes involved in the genome maintenance may increase its imperfect nature, possibly in a tissue-specific manner, but might never completely mimic normal aging.
Hence, the accelerated aging symptoms in humans and mice with genetic defects in genome maintenance strongly suggest that genome instability, driven by oxidative damage, is a primary cause of normal aging.
Genotype-phenotype correlations in mouse models of defective genome maintenance can provide valuable insights into basic mechanisms of aging and the natural defense systems that promote longevity.
Such studies can also provide the groundwork for engineering improved DNA maintenance pathways.
In turn, this will facilitate genetic or pharmacological interventions that reduce DNA damage, promote repair or optimize the cellular responses to DNA damage to prolong healthy life and delay aging.