1.
Genetics
Among gerontologists concerned with genetic approaches to aging and longevity, there is somewhat of a dichotomization (10). “On the one hand, there are those, who tend to be the 'complificationists', very impressed by the enormous diversity of genetic modulations of human senescence and who believe that senescent phenotypes per se are non-adaptive, non-determinative, subject to stochastic events as well as highly polygenic modulations, with a resulting wide variability in mechanisms of senescence among and within species.
On
the other hand, there are those who seem to be convinced that there are likely
to be a rather small number of major gene effects for a few major mechanisms.
They include Saccharomyces cerevisiae
and Caenorhabditis elegans
geneticists, some Drosophila
melanogaster geneticists. They also include caloric restriction
enthusiasts” (10). Where does the truth lie ?
A
good way to try to investigate the genetic basis of longevity is to study
the centenarians, because all of them share something in common: having survived
the vicissitudes of life through a combination of robust physiological, psychological,
and social strengths; having escaped from disease processes that shorten life
and benefited from simple good fortune (11). They
probably have the optimal set of genetic factors necessary to
get to 100 years and beyond (12). Numerous
are the data coming from the “search of the genetic secret of the centenarians”.
New hypotheses appear interesting because they link longevity and disease-free
life expectancy:
Inheritance of at least one Apolipoprotein E2 allele appears to promote longevity even among centenarians. The resulting lower level of cholesterol linked to low-density lipoprotein could be protective from both time- and age-related atherogenesis and cardio-vascular diseases (11).
Mitochondrial DNA (mtDNA) haplogroup J is significantly over-represented in healthy centenarians with respect to younger controls, thus suggesting that this haplogroup predisposes to successful aging and longevity. But, the same haplogroup is reported to have elevated frequency in some complex diseases (for example: Leber hereditary optic neuropathy). This finding implies that the same mutations could predispose to disease or longevity, probably according to individual-specific genetic backgrounds and stochastic events (13).
Genetic modulations of lifespan may involve four different kinds of somatic genes (14):
-
Good genes with early and late good
effects (longevity assurance genes)
-
Good genes down-regulated for good
reasons (developmental program genes)
-
Good genes with only bad effects late in
life span (agonist/antagonist pleitropy
genes)
-
Bad genes or slightly bad genes that do
not show their true colours until late in life (accumulation of constitutional mutations)
Among
these categories of genes, two interfere mostly with the quality of aging:
Firstly, good genes with only bad effects in late life span (agonist/antagonist
pleitropy). Cancer of the prostate provides a good example. A high
androgen receptor sensitivity is linked with a high risk of prostate cancer.
But the reverse is also true: a low androgen receptor sensitivity is linked
with a low risk of prostate cancer. The main genetic difference between these
two possibilities is the length of the CAG sequence (11 in the first case and
33 in the second). Secondly, bad genes or slightly bad genes that do not show
their true colours until late in life (accumulation
of constitutional mutations) are probably the genetic key to many
neuro-degenerative diseases such as Hutington disease, amyloidosis process and
probably Alzheimer disease (14).
In parallel it appears that a long life depends on the timing of maturation but also on the quality of the somatic maintenance. One broad-based hypothesis is that an imperfect genome maintenance of deoxyribonucleic acid (DNA) damage is a possible causal factor in aging. Errors during repair, replication or recombination of a damaged DNA template may lead to the accumulation of mutations (15). These mutations in genomic DNA result in the gradual alteration of cellular function, exhibited in a variety of tissues and provoke a progressive but generalized homeostatic failure leading to the age-related decline (15).
Damage to DNA is one centrepiece of most theories of aging (16). Evidence is also accumulating that telomere shortening is associated with cellular senescence in vivo. Located at the ends of eukaryotic chromosomes and synthesized by telomerase, telomeres maintain the length of chromosomes (16). In fact, the telomeric structure prevents the degradation or fusion of chromosome ends and thus is essential to maintain the integrity and stability of eukaryotic genomes. Telomeres also allow cells to distinguish the chromosome ends from double strand DNA breaks. In addition, and perhaps less widely appreciated, telomeres may also indirectly influence gene expression (17). In both genders, telomere length was inversely correlated with age. The longer telomere in women suggests that for a given chronological age, biological aging of men is more advanced than that of women (18). At each mitosis it seems that the cut part of telomere is greater in men than in women. This finding is so important to explain the difference in gender longevity that it needs to be confirmed by larger studies in various aged populations. As it will be stressed below, there is also increasing evidence that oxidative damage is an important factor leading to the shortening of telomeres, induction of mutations in genes, and damage to mitochondrial DNA. The association between cellular senescence and telomere shortening in vitro is well established. In the laboratory, telomerase-negative differentiated somatic cells maintain a youthful state, instead of aging, when transfected with vectors encoding telomerase. At this stage it is logic to think that the key to "youthfulness" perhaps lies in our ability to control the expression of telomerase (16). But, telomerase activity is a mechanism that most normal cells do not possess, whereas almost all cancer cells acquire, to overcome their mortality and extend their lifespan (19).
The existing links between genetics, oxidative metabolic damage and diseases appear as one of the most challenging difficulty to explain longevity and understand the aging process and its related alterations.