Why do we age?
Our bodies repair themselves all the time, yet with the years they wear out. Why doesn't evolution prevent it?
The question
Everyone ages. With time, the body repairs itself less well, tissues lose their function, and the risk of almost every serious disease rises steeply. After about age 30, a person's risk of dying roughly doubles every eight years.
This is less obvious than it seems. A body is not a machine that wears out like a car: it constantly rebuilds itself, replacing cells and molecules. An embryo, built from an adult's cells, starts with a fresh body. And some animals barely seem to age at all. So why do we? There are two separate questions here: why evolution allowed ageing to exist, and what actually happens in the body as we age.
What we know
- Why evolution allows it. In 1952 Peter Medawar pointed out that in the wild, most animals die young from predators, accidents and disease. Natural selection therefore barely acts on what happens late in life, so harmful effects that appear only in old age can accumulate. In 1957 George Williams added that genes useful in youth can be favoured even if they cause harm later. These ideas are widely accepted.
- Ageing varies enormously. Mice live two or three years, naked mole-rats of similar size more than 30. Greenland sharks may live centuries. Some animals, such as certain tortoises and some species of freshwater hydra, show little or no increase in death rate with age.
- It can be changed. Single mutations in the worm C. elegans can double its lifespan, as Cynthia Kenyon's lab showed in 1993. Eating less without malnutrition extends life in many laboratory animals. In mice, removing old "senescent" cells, which stop dividing but remain and release inflammatory signals, improves health and extends life.
- Cells keep a record. Chemical marks on DNA change with age so regularly that "epigenetic clocks" can estimate a person's age from a blood sample within a few years.
- Cells can be reset. In 2006 Shinya Yamanaka showed that four factors can turn adult cells back into embryonic-like stem cells. Partial versions of this reprogramming have made old cells and tissues in mice behave younger.
- In 2013 researchers summarised the cellular changes of ageing as "hallmarks": damaged DNA, shortened telomeres, misfolded and clumping proteins, failing mitochondria, senescent cells and others. In 2023 the list was extended to twelve.
Main hypotheses
Accumulated damage
Ageing is the build-up of many kinds of molecular damage that repair can't fully keep up with. Each hallmark is a form of this damage. On this view, there is no single cause.
A programme
Ageing is partly a continuation of development: genetic programmes useful in youth keep running and become harmful later. The epigenetic changes and their partial reversibility support this view.
Trade-offs
The body has limited resources and must balance reproduction against maintenance. Species and individuals differ in how they divide this budget, which explains the huge differences in lifespan.
Where understanding ends
We have a long list of what changes with age and many ways to extend life in laboratory animals. We don't know which of the changes are causes and which are consequences, or whether there is a central process behind them. The hallmarks are interconnected, and changing one changes the others.
There is also the question of measurement. Epigenetic clocks track age remarkably well, but it is unclear whether they measure ageing itself or only something that accompanies it. Without a reliable measure, it is hard to test whether a treatment really slows ageing in people within a reasonable time.
And results in animals have been hard to transfer to humans. Whether calorie restriction or drugs that mimic it extend human life is unknown. The many companies promising to slow or reverse ageing have so far shown no treatment proven to do so.
What would settle it
- Identifying which hallmarks drive the others, by changing one at a time in animals and seeing what follows.
- A validated measure of biological age that predicts health and death, so that treatments can be tested in people.
- Understanding how long-lived species, such as naked mole-rats or bowhead whales, avoid the decline we experience.
- A treatment that demonstrably extends healthy human life in a controlled trial.
Sources
- Medawar, P. B. (1952). An Unsolved Problem of Biology. H. K. Lewis, London.
- Williams, G. C. (1957). Pleiotropy, natural selection, and the evolution of senescence. Evolution, 11(4), 398–411.
- Kenyon, C., et al. (1993). A C. elegans mutant that lives twice as long as wild type. Nature, 366(6454), 461–464.
- Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676.
- Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome Biology, 14(10), R115.
- López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194–1217.
- Jones, O. R., et al. (2014). Diversity of ageing across the tree of life. Nature, 505(7482), 169–173.
- Baker, D. J., et al. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184–189.
- López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: an expanding universe. Cell, 186(2), 243–278.