The process of aging – a nearly universal phenomenon – has long been at the forefront of humankind’s curiosity and imagination. Our ability to observe the aging process has played a pivotal role in the development of human culture and society. In early civilizations, humans who lived to an old age were seen as wise, often becoming societal leaders or given major responsibilities. In present day, a vastly increased human life expectancy allows us to appreciate the major need for improved medical and social services for the elderly. With aging having a profound impact on the perception of health management, human welfare, and more broadly on life itself, it’s important to first understand what exactly aging is.
THE MECHANISM BEHIND LIFE’S DECLINE
Aging is typically experienced as a gradual loss of physiological integrity and impaired bodily functions; however, the exact mechanisms behind this complex biological deterioration are still not fully understood. One of the major factors associated with aging is an accumulation of genomic damage throughout life; DNA encounters exogenous chemicals and toxins, as well as endogenous threats such as replicative errors and reactive metabolites that dampen their integrity. Fortunately, complex networks of DNA repair pathways are capable of repairing most DNA lesions. These repair pathways are imperfect, and there is strong evidence that the accumulation of this genomic damage accompanies aging. In fact, many premature aging diseases (e.g.: Bloom Syndrome, Werner Syndrome) occur as a result of increased DNA damage.
One cellular function that likely plays a large role in aging is the maintenance of protein homeostasis. Proteins carry out vital functions for proper cellular activity; critical to effective protein function is proper protein folding and stability, to which the body has developed various quality control mechanisms. It may come as no surprise that maintenance of proteostasis is altered with aging – specifically, the chaperone system experiences dysregulation as we grow older. Chaperone proteins are a family of proteins that function to assist with protein folding and stability. The ability to synthesize these stability proteins in response to stress is lost with aging, which reduces our ability to combat cellular damage over time. Notably, over-expression of chaperone proteins in worms has been shown to increase their longevity. Many age-related pathologies such as Alzheimer’s and Parkinson’s disease are actually due to chronic exposure to misfolded or aggregated proteins; thus, proper maintenance of proteostasis seems to have a major role in biological aging.
Epigenetic modification to the genome represents another cellular process implicated with aging. Epigenetics involves heritable changes to gene expression that do not occur as a result of direct changes to the genomic DNA sequence. One notable epigenetic modification linked to aging is histone modification. Histone modifications represent a post-translational change to the histone proteins which participate in organizing DNA, typically through the addition of a phosphate, acetyl or ubiquitin group. There is strong evidence to suggest a role for histone modification in aging, as it has been shown that inhibition of specific histone modifying enzymes can result in increased longevity of invertebrates such as yeast, worms, and flies. Similarly, inhibition of homologs of these enzymes has shown to enhance the health of aging mice. Although there is still much to learn, there is an abundance of evidence to support the idea that aging is accompanied by epigenetic alterations to the genome.
Finally, one of the most well studied biological processes thought to contribute to aging is telomere shortening. Telomeres are repetitive nucleotide sequences located at each end of every chromosome; they function to protect chromosomes from accidental fusion or DNA damage. Most DNA polymerases lack the ability to completely replicate to each chromosomal end, resulting in the progressive loss of telomere sequences with each cell cycle. When telomere sequences are fully lost, so too is the cell’s ability to replicate, rendering it inactive; telomere exhaustion is thought to be one of the major contributors to cellular senescence. Telomerase is a DNA polymerase capable of fully replicating telomeric sequences; however, this enzyme is expressed solely in stem cells and cancer cells. Ectopic expression of telomerase in somatic cell lines has been shown to grant immortality in culture, and genetic modification of telomere length or forced expression of telomerase in mice has been shown to enhance their longevity. Overall, the shortening of telomere sequences is strongly associated with cell inactivity, and seems to be characteristic of biological aging.
As we begin to parse the complex cellular and molecular mechanisms that contribute to and promote biological aging, we may one day be able to apply this insight into improving human health during aging and better treatment of age-related diseases.
ARE WE PROGRAMMED TO DETERIORATE?
While many of the mechanisms of aging seem to be due to the accumulation of genomic damage or breakdown of regulatory pathways as we age, some theories have proposed that these processes are actually pre-programmed biological events. One celebrated idea of programmed senescence is that of V.P. Shukalev and his theory of phenoptosis – the notion that the death of an organism is programmed by its genome. There is certainly evidence to support this idea; in the wild, for example, senescence seems to be induced very abruptly following reproduction. This can be seen most dramatically in the life cycle of salmon. Salmon spend their adult life in the Pacific Ocean and then undergo mass migration into fresh water rivers to spawn. Following spawning, the salmon undergo a period of rapid deterioration and eventually die, supporting Shukalev’s claim.
While this theory certainly helps to explain the spontaneous senescence observed in many organisms following reproduction, it does not fully explain the actual temporal process of aging. Any organism, including salmon, could fail to reproduce or avoid reproduction and yet would still be bound by the average biological lifespan of their species. Because of this, most of the currently accepted theories of aging are focused on genetic trade-offs and optimal resource management as being the major contributing factors for an organism’s average lifespan.
For example, the disposable-soma theory is based on the optimal usage of an organism’s resources for to balance between self-maintenance and reproduction. If an organism is under heavy predation, there is little benefit to genes linked to longevity. This organism can instead invest heavily into genes and resources that may enhance its early life survival, allowing it to reach sexual maturity and paying little mind to long-term self-preservation. This idea of trade-offs playing a role in lifespan programming can be appreciated when comparing the average lifespan of various species to their risk of predation; hunted animals, such as mice, have shorter biological lifespans than their hunters, such as a fox.
To date, scientific research has uncovered a wealth of information regarding the specific cellular and molecular mechanisms of aging. We now have an understanding of how many cellular processes, such as genome modification and protein homeostasis, may contribute greatly to the aging process. We are also beginning to understand the evolutionary forces behind aging, and how the aging process can be programmed within the genome to control an organism’s overall longevity. Further research into these biological mechanisms and the impact of specific genes on longevity may one day enable us to have better control over aging-related pathologies and potentially enhance the overall lifespan of humankind.
- López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Cell. 2013;153(6):1194-1217. doi:10.1016/j.cell.2013.05.039.
- Kim D-K, Kim TH, Lee S-J. Mechanisms of aging-related proteinopathies in Caenorhabditis elegans. Experimental & Molecular Medicine. 2016;48(10):e263-. doi:10.1038/emm.2016.109.
- Montpetit AJ, Alhareeri AA, Montpetit M, et al. Telomere Length: A Review of Methods for Measurement. Nursing research. 2014;63(4):289-299. doi:10.1097/NNR.0000000000000037.
- Sergiev PV, Dontsova OA, Berezkin GV. Theories of Aging: An Ever-Evolving Field. Acta Naturae. 2015;7(1):9-18.
- Kirkwood TBL, Austad SN. Why do we age? Nature. 2000; 408: 233-238.
- Shukalev VP. What is ‘Phenoptosis’ and how to fight it? Biochemistry (Mosc). 2012; 77(7):689-706.
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