Most people think of aging as passive – something that happens to your body. Random mutations occur faster than the body can fix them. Cholesterol deposits build up in the arteries. Above all, oxidation damages the body’s delicate chemistry, and this affects the ability to fix other damage.
But a new view is emerging, in which aging is an active process. Much of the damage appears avoidable, if only we kept churning out the same hormones we did when we were young, instead of changing to a less effective mix as we get older. Worse – some systems actually turn against the body, destroying perfectly good tissue, as if “on purpose”. There are four such processes: inflammation, immune derangement, cell suicide (or apoptosis) and telomere shortening. They make promising targets for new anti-aging research. More on this next week.
What’s up with evolution?
It has been a surprise for evolutionary biologists in recent years to discover that there are genes that regulate aging. More curious yet – some of the genes for aging have been around for at least half a billion years, from a time when eukaryotes (nucleated cells) were new on earth. Usually, evolution is very good at holding on to what works, and getting rid of genes that are harmful. Aging ought to be in the second category – aging destroys fitness. Why would evolution preserve harmful genes and pass them on?
This sounds like a question for theorists, or even philosophers. But the question has taken on a practical importance now that biochemists know how to turn genes on and off. Should we turn off the aging genes? Would terrible things happen to us as a side-effect – sterility, or maybe cancer? Or would this be the shortcut we’ve all been waiting for – a new and more effective path to life extension?
Discovery of Genes for Aging
Nematode worms, fruit flies, and yeast cells are the most common lab organisms used to study aging because their life spans are conveniently short. Beginning in the 1990s, geneticists knew how to identify individual genes and remove them – mutate or snip them out from an egg cell, which contains a single copy of the genome that will be replicated into every cell of the adult. Here was a surprise that transformed aging science: for each of the three lab organisms, there were genes that could be removed, causing the animal to live longer. What is more, these genes were closely related, underscoring the inference that they were no accident, but a surprising and paradoxical product of evolution. A common genetic basis suggested that what we learned from simpler animals might also apply to humans.
Some of the earliest genes discovered to regulate aging were related to the insulin metabolism, and presumably mediate the mechanism by which aging is slowed by caloric restriction (or shall we say, “aging is accelerated by abundant food”?) In worms, DAF-2 was one of these genes.
It was natural to ask about the metabolic effects of DAF-2: what is its role in the metabolism? The Harvard laboratory of Gary Ruvkun was able to prepare “mosaic” worms that had different genes in different parts of their bodies. Before asking “how”, it would be interesting to know “where” DAF-2 was acting. Ruvkun and team tried mutating DAF-2 just in the muscles. No life extension. They repeated the experiment with DAF-2 mutated in just the digestive system. No life extension. But when DAF-2 was disabled in the nerve cells, that was sufficient to double the worms’ life span. The nervous system suggested signaling and active, intelligent control. This finding helped to solidify the new paradigm: life span is actively regulated by the body.
Sharpening the evolutionary paradox
Here’s a detail that underscored the evolutionary paradox: The principle that “natural selection can only generate adaptations that are good for an individual’s fitness” is so fundamental to evolutionary theory, that theorists looked for an interpretation of the data that would support this axiom. The axiom might still be true if these preserved genes were selected for some powerful benefit, such that accelerated aging was a side-effect of genes whose primary effect was beneficial. This theory goes by the name antagonistic pleiotropy, and was first proposed by George Williams back in 1957.
The gene DAF-2 did indeed have benefits, and the long-lived mutants appeared fat and lazy. But the benefits appeared when the gene was turned on in muscle cells, while the life-shortening effects came from the gene’s presence in nerve cells. It is normal for gene expression in different tissues to be separately regulated. Ruvkun emphasized that the costs and benefits were easily decoupled. If he could separate the two effects in a simple lab manipulation, why hadn’t nature learned to do the same over the aeons?
Evidence accumulates for active aging
The more we learn about the physiology of aging, the clearer it becomes that the standard evolutionary view doesn’t work. Two of the body’s systems that are highly evolved for self-protection morph, as we age, into means of self-destruction. These are inflammation and apoptosis. It is common to speak of this as “dysregulation”, as though it were just a mistake. But you have to wonder about such costly mistakes. Natural selection ought to be quite efficiently weeding them out.
Inflammation is the body’s first line of defense against invading microbes, and it also plays an important role in eliminating diseased cells and damaged tissue in wounds and bruises. However, as we get older, inflammation turns against the body. Inflammation in cartilage is the proximate cause of arthritis, and in our arteries, inflammation creates the plaques which can lead to heart attacks and strokes. Inflammation damages DNA, and can turn healthy cells into cancers.
Apoptosis is the biologists’ word for cell suicide. It is vitally important to be able to get rid of cells that are unneeded, or cells that have become diseased or cancerous. We need apoptosis, and would be more vulnerable without it, but as we get older, apoptosis develops a “hair trigger”, and cells begin to commit suicide when they’re still healthy and useful. Overactive apoptosis is to blame for sarcopenia – the loss of muscle mass with age. Apoptosis is also implicated in the loss of brain cells that leads to Alzheimer’s Disease.
A third self-destruction mechanism is cellular senescence. This is the telomere metabolism, which I discussed in two earlier posts here and here. Unlike inflammation and apoptosis, cellular senescence serves no useful purpose for the body. (Theorists have proposed a role for telomeres in cancer prevention, but it has turned out that animals and people with short telomeres have consistently higher risk of cancer.)
As a strategy for research, study of the body’s signaling holds the best promise for big strides in life extension. We can work at fixing what goes wrong, engineering solutions to the damage that appears at many levels, and in many tissues as we age. But if much of this damage is self-inflicted, it will be easier to prevent it than to fix it. The fact that aging is highly regulated suggests it should be possible to modulate aging from the top down by intervening in the regulatory chemistry.
Evolutionary theorists are still adamant that aging could not have evolved as an adaptation, but their theory is holding back progress. One of these days they will have to face the overwhelming evidence that aging has evolved as an active process of self-destruction. Both evolutionary theory and geriatric medicine will be profoundly affected.