The biology of ageing
Nearly all organisms, from the mighty E.coli to the humble human, experience some form of ageing. Defined as the intrinsic, progressive, and generalised physical deterioration that occurs over time, ageing is ubiquitous and yet far from well understood.
Why do we age anyway? On the face of it, it would seem that a longer lifespan would be advantageous. More time on the planet means more time to procreate and produce more offspring, thereby improving evolutionary fitness, right? Evolutionary biology refutes this succinctly: in the natural world, animals die from predation and accidents. There is an extrinsic limit to their expected lifespan. Any genes that would confer fitness and longevity beyond this expected lifespan are largely ignored by natural selection because the animal dies—by accident or by dinner time—before the genes can confer a selective benefit. Maybe there is a gazelle out there with the genes to live forever, but its odds of being devoured by the leopard around the corner far outweigh its chances of living beyond its brethren.
As such, longevity tends to only be selected for when a species decreases its extrinsic mortality rate, which explains why larger animals tend to have longer maximum lifespans than smaller animals and why birds have longer maximum lifespans than similarly-sized wingless species. Grow larger, evolve wings, or move to an environment with fewer predators, and your risk of predation or accident falls and your species can select for genes that grant a longer life.
Not only are humans lucky enough to avoid predation (for the most part), we are also fortunate enough to see huge gains in average life expectancy. In the United Kingdom, the average lifespan for a woman has jumped from 52 years to 82 years in under a century. We live much longer lives than our ancestors thanks to steady improvements in diet, healthcare, and living conditions, and the lack of saber-toothed tigers on our daily commute.
Getting older involves the body wearing out. The skin loses elasticity and wrinkles. Bones become brittle and muscles become weaker. Memory fails and the immune system becomes less effective at battling disease. 100 million million cells make you you. Some of them are constantly replaced, as existing cells multiply to make new ones—skin is a prime example. Others are rarely replaced, such as those in the brain. Each cell, regardless of its type, can only multiply a certain number of times before it dies. Telomeres are the areas at the end of the chromosomes that become slightly shorter every time a cell divides: run out of telomeres and the cell stops dividing and eventually dies. This is the Hayflick limit, the number of times a normal human cell will divide before cell division stops (senescence). The normal limit for a human cell is between 50 and 70 divisions.
Telomerase is an enzyme that can add length to the telomeres and is found in gametes and normal stem cells. It allows each new cell progeny to replace the bit of DNA it lost from its parent cell, allowing that line to divide without ever reaching its limit. This same unbounded growth is a feature of cancer.
As we age, our cells become less efficient at repairing themselves after damage. Free radicals and glucose, both by-products of energy production in the body, batter the cells continuously. Eventually, cells become permanently damaged.
Allowing old or damaged cells to carry on growing and dividing forever would have disastrous results. Ageing is a bodily fail-safe with the unfortunate eventual consequence of death.
There are several major hallmarks of ageing with telomere attrition just one. Genomic instability, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication have all been experimentally shown to drive ageing phenotypes in multiple organisms. Understanding how these pathways work and how they are perturbed over time is critical to designing interventions to slow, stop, or reverse the ageing process.
Why do these things have to happen? There are a few different theories with mutation accumulation theory, antagonistic pleiotropy theory and disposable soma theory the most widely accepted in the biological community. None of these are mutually exclusive, by the way. Mutation accumulation posits that ageing is a matter of random, germline mutations occurring over time and proving detrimental to overall health and survival. Enough deleterious mutations and cell senescence is inevitable. Antagonistic pleiotropy suggests that one gene may create two traits: one is beneficial and one is detrimental, with the benefits conferred to early life, and accumulating a detrimental cost in later life. While antagonistic pleiotropy is a prevailing theory today, research has shown it’s not true for all genes. The third mainstream theory is disposable soma theory where the body has a limited amount of energy available to it and must compromise where it spends its resources. When the body runs out of energy for the repair function, it gradually deteriorates.
Which theory is right matters immensely, as that determines how we can push the limits of ageing.
There is so much variability in ageing across species. Some live for a very long time, others are more fleeting. It is a mysterious and multifarious process, but remains a fact of life. We all grow old but even within our own species, we all age in different ways. Previous studies have found that approximately 25 percent of the variation in lifespan is caused by genetic factors, but since ageing is so extraordinarily complex, biology alone cannot account for how we age. Social factors and health behaviours also have a great influence on ageing processes and lifespan with recent research suggesting that strain throughout life affects the ageing process. Ageing isn’t just a bodily process; it’s a societal one. It’s a class problem.
With so many influences, the inevitable (and unsatisfying) conclusion of all this is that the jury is still out regarding the mechanisms of ageing. Two things are certain: we will all age and life is one big game of probability. ■