Why Do We Age?

The Evolutionary Context of Senescence

People have rationalised aging and the inevitability of death throughout the past as ‘only natural’, ‘For the good of the species’ or as ‘Making way for the next generation’. Taking a closer look at the evidence though quickly makes it plainly clear that these explanations are simply wrong. In a typical natural environment organisms die through predation, accident, starvation, infection and other such events long before aging becomes a factor [20]. Aging, as a general rule, has virtually no influence in the natural world, and it this fact precisely that explains how it is that aging arose in the first place.

In 1957 Williams wrote a paper called “Pleiotropy, Natural Selection, and the Evolution of Senescence” which built on the idea introduced in 1952 by Medawar [14] that evolution would not be able to exert any real selective pressure on genes which act after the reproductive age. Williams proposed a more practical idea, that genes which produce an advantage early in life but have a later acting negative effect would still be selected regardless of the later effect. He claimed that “natural selection may be said to be biased in favour of youth over old age whenever a conflict of interest arises [20].” This theory, known as ‘Antagonistic Pleiotropy’ has since been expanded once more by Kirkwood in 1977 with the addition of the ‘Disposable Soma Theory’ [10]. This latest addition picks up on the bias natural selection has for youth and suggests that organisms evolve in a way which puts as many resources into ensuring youthful vigour and reproductive success as is required, and only after these two facets are assured do any resources get distributed into maintaining the somatic cells. In other words, evolution cannot select long living individuals if they are going to die before reproduction anyway. Evolution recognises that the body is disposable and so allocates resources appropriately.

These theories are important because they form a basis from which investigations into the mechanisms of aging can be approached from. These theories imply that it is unlikely for there to be any genes ‘for’ aging as such, but instead there will actually be genes ‘against’ aging. They imply that the causes of aging will actually be side effects of otherwise beneficial genes. They also imply that the genes associated with longevity will actually be genes which affect the durability and maintenance of the somatic cells [11].

The Free Radical Theory of Aging

The Free Radical Theory of aging has become one of the main focuses of aging research today. The theory proposes that reactive oxygen species (ROS – The ‘Free Radicals’), largely produced as a side effect of normal mitochondrial metabolism, cause progressive damage resulting in the functional decline that defines aging [4]. A lot of evidence for the theory is apparent in the fact that most lab organisms which have had an increased life span, have also been shown to have an increased oxidative stress response [2][13][19].

The overwhelming correlation between increased stress response and increased lifespan has an incredibly strong implication that ROS may cause some aspect of aging. The stress response which combats the ROS, extending lifespan, happens to be a perfect example of the expected type of relationship to form under the Antagonistic Pleiotropy theory. Aerobic metabolism undoubtedly evolved shortly after the mass extinction of most obligate anaerobes was caused by the flooding of Earth in O2 from Cyanobacteria photosynthesis. The surviving bacteria must have had some sort of oxidation resistance already, but those which utilised their existing photosynthetic electron transport chains to extract energy from the newly abundant energy source of O2 would have had a much larger advantage over its anaerobic competitors [3].

The evolution of aerobic respiration was undoubtedly beneficial in its context and the basic control of oxidative damage was already set up, while the accumulation of damage from the occasional escaped superoxide particle was unlikely to have any noticeable deleterious effect on the quickly replicating bacteria. It isn’t until evolutionary history proceeds, conditions change, life expectancies change as complexity increases, and the small amounts of damage become increasingly important. The evolution of increasingly efficient antioxidants is the only method available to counteract this side effect of an otherwise incredibly beneficial gene.

This hypothetical story may not be completely accurate, but the evidence does support something at least similar. Overexpression of the genes for superoxide dismutase (SOD) and catalase in Drosophila, the two primary ROS scavenging enzymes, increases lifespan by around 34% [9], demonstrating both the effect ROS may have on lifespan, as well as the importance of controlling the ROS. More interestingly, overexpression of just the human SOD1 gene increased its lifespan by 40% [9], implying the more effective scavenging ability of the human SOD enzyme which would be expected in a longer living organism. age-1 mutants in C. elegans live twice as long as the controls and were found to also increase SOD and catalse activity [9], while the Methuselah mutant Drosophila also demonstrated increased resistance to oxidative stress, high temperature and starvation, and lived 35% longer than their parent strain [13]. Both of these examples also show how counteracting the ROS may be incredibly influential in longevity.

Having said that, an important criticism raised recently by Spencer et al [19] about the quality of specimens used for longevity comparisons may just undermine exactly how meaningful an ‘extension’ of 30-50% in lifespan may be. The breeding techniques employed in labs to maintain their stocks of Drosophila, results in a selection pressure for rapid reproduction and large litters [15]. The Disposable Soma Theory states that this would create an evolutionary pressure to direct resources to those areas at the expense of soma durability and maintenance. Spencer et al demonstrated that the extension in life from overexpression of SOD was in fact dependent on the genetic background the specimen was taken from, showing some results which had a noticeable increase in longevity, and occasional results which actually decreased longevity. Perhaps naturally living Drosophila naturally ‘overexpress’ SOD and catalase already?

Whatever the case may be, it seems reasonable enough to accept that ROS plays a key role in aging, and Antioxidant enzymes like SOD play a key role in controlling ROS. Whether this information can be used to actually extend lifespan or improve the average quality of life in older age is far from certain, but at least we have something to work with.

Other Theories on Aging

Far from being the only theory on aging though, the Free Radical Theory is only one of many theories. There is the alternative version of the Free Radical Theory, the Mitochondrial Theory of aging, which uses the ROS idea in a vicious circle where damage to the Mitochondrion causes more ROS to be created, resulting in an exponential increase in oxidative damage [7]. This theory has lost favour in more recent times, though still attracts interest [7][16][8]. Genome Instability, the accumulation of mutations, rearrangements and changes in chromosome number have been proposed as another cause of aging [9], while an offshoot of this theory is based on the accumulation of ribosomal DNA loops which bud out of the genome then proceed to replicate themselves, growing in number and eventually causing fragmentation of the nucleolus [18]. This has only been observed in S. Cerevisiae though so has little following as a general theory of aging. Research into the WRN gene, the gene responsible for the human progeria disease Werner Syndrome, has implicated the function of DNA Helicases and their actions in suppressing DNA recombination in aging [9]. Genetic programs for aging based on genes found in C. elegans [9], accumulation of potentially harmful abnormal proteins [12], and the cell death theory which claims that gradual loss of cells in postmitotic organs eventually leads to degeneration, are all offered as aging theories. A theory of Systemic Control of aging in the body by something such as the endocrine system has been suggested with evidence from C. elegans. Apfeld and Kenyon (1998) demonstrated that a small number of mutant cells could confer increased lifespan to the entire animal [9], believing that this meant that the gene in question produced a secreted factor which dictated the pace of aging.

An important implication from all these theories and all of the research done on these theories over the years is becoming more and more clear: It is unlikely that we are going to find ‘The’ cause of aging. Even if a systemic control factor of aging is discovered, it is unlikely to provide a simple way out of aging. Assuming we could just trick the body into behaving like it was 18 years old, we would still have to deal with the accumulation of oxidative damage, the loss of postmitotic cells, the risks of cancer, heart disease and other diseases of accumulation/degeneration.

Telomeres

Now implicit in the cell death theory of aging, Telomeres have gained particular notoriety as the biological clock of aging. In 1961 Hayflick and Moorhead reported the limited number of replication events human fibroblasts could go through before entering a quiescent, viable state, unable to enter further rounds of replication [6]. This number of replications was called the ‘Hayflick Limit’ and was explained in 1990 when Harley claimed that Telomeres act as the counting mechanism which limit the replication of the fibroblasts [5].

Telomeres serve several functions in the genome, some of which include solving the “end-replication problem” [1], preventing end-to-end fusions of chromosomes, and preventing exonucleolytic degradation. Telomerase is an enzyme produced by cells which lengthens telomeres, counteracting the shortening of the end-replication problem, but it is not active in somatic cells in humans. Why not? It is most likely not active because it gives too much freedom for rogue cells to turn cancerous and threaten the entire body. The control over every individual cell by the body is incredibly important, and if a cell breaks free of that control, then the inevitable death of that cell is important.

These functions of telomeres are all now unavoidable. As long as we have linear DNA, replicate our DNA through DNA polymerase and exist as a multicellular organism, we need telomeres. The apparent link to aging is unfortunate and stands once again as an example of Antagonistic Pleiotropy.

Interestingly, evidence has shown oxidative damage itself may directly cause telomere shortening [17]. This fact reiterates the confusing intermingling of aging mechanisms faced by researchers, further highlighting the unlikelihood of ever finding a single ‘cause of aging’.

Conclusion

Understanding aging will be a matter of understanding Cell Biology as a whole. The evidence so far seems to be loud and clear that there is no such thing as a single cause of aging let a lone a single solution to it. Instead the evidence implies that aging is just an accumulation of complex side effects piled on top of each other in a somewhat random uncontrolled way, resulting in all sorts of nasty phenotypes that most just wish to avoid. Perhaps when our understanding of Cell Biology reaches a high enough level we will be able to design novel solutions for the issues which cause aging, but until that time all you can do is restrict your calorie intake and avoid standing in the middle of major roads in peak hour.

References

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