What causes the activation of "Late acting deleterious genes" in late age but not in young age, whose accumulation causes ageing according to Medawar?

Question

Sir Peter Medawar proposed that aging is the byproduct of "late acting deleterious genes". Evolution is good at weeding out genetic mutations that are harmful at an young age, before the organism has a chance to reproduce, because the organism will not survive to pass on those genes (genes that are weeded out are genes that reduce fitness, confer disability and generally reduce chance of living long enough to reproduce). However, genes that exert their effect at a later age pass through the sieve of natural selection, because natural selection cannot act on them. According to Peter Medawar it's the accumulation of such late acting deleterious genes that causes aging.

I have two questions: What kind of "genes" are we talking about (whose accumulation in late age and its deleterious effects lead to ageing)? Genes with some essential function at young age: such as genes involved in reproduction, survival, functioning of organs etc - or "neutral" selfish genes (i.e genes that are "neutral"or have non-essential functions during the organism's youth, but individually mildly deleterious during late age) that kind of "hitched a ride" to the next generation? These kinds of "neutral genes" could arise over evolutionary time simply due to genetic drift?

Second question: What causes these late acting genes to become activated at late age (but not at young age)? Epigenetic landscape in late age, internal biochemistry? Is there any experimental evidence, and examples of such genes? I am guessing they are mildly deleterious on their own but collectively debilitating.

Answer 1

It's not that genes become 'activated' at late age, but that they aren't relevant until late age, so high performing versions aren't selected for and poor performing versions aren't selected against. As for which genes, we can see some in the answers to another question, What is the longest-lasting protein in a human body?

The accepted answer is crystallin, in the lens in your eye. These proteins eventually cross-link and degrade, leading to cataracts and blindness, which decreases fitness. Newts can regenerate their lenses, and more stable versions that take longer to degrade could presumably exist, so it's biologically possible to avoid this loss of fitness. However, doing so wouldn't affect the fitness in the first ~50 years of life, so selection can't maintain those mechanisms against genetic drift.

Crystallin is one example of long-lasting proteins, and those are just one example of how genes can have fitness costs that don't reveal themselves until late in life. When 'accumulation' is used in the context of Medawar's hypothesis, it refers to the accumulation in the population over many generations of these late-acting mutations, because natural selection can't remove them the way it can early-acting mutations.