In his new book, Cracking the Aging Code: The New Science of Growing Old and What It Means for Staying Young, Josh Mitteldorf, who has studied aging for decades and writes about it at his website, explores the science of aging and sets forth his own theory as to why we, and virtually all organisms above the level of bacteria, age. (The book has a co-author, Dorion Sagan, but the theory is Mitteldorf’s, and in any case, perhaps because I’ve been an avid reader of his website, the author’s voice seems like Mitteldorf’s alone.)
This is the science book of the year, the best I’ve read in quite awhile.
Mitteldorf is an expert in evolutionary theory (he used to be an astrophysicist), and deftly and skillfully expounds and criticizes the several current theories of aging. He then proposes his own radically different theory. And he’s very convincing. Whatever the fate of his theory, he brings enough evidence to bear both in its favor and against the other theories that, it seems to me, his theory must be reckoned with.
Aging has been a thorn in the side of evolutionary theory since the beginning. Even Darwin knew and understood this and could not see a way to incorporate aging into the theory of evolution.
Aging poses a conundrum for evolutionary theory because aging manifestly decreases biological fitness, causing lower reproduction and greater mortality. Why wouldn’t evolution have abolished it, or not allowed it to come into existence?
If an organism didn’t age, it would seem to have an advantage: it would never die of aging and it would continue to reproduce throughout its lifetime; hence the longer an organism lived, the more offspring it would leave, and the fitter in evolutionary terms it would be.
Indeed, we do see this in some organisms. Lobsters, for example, apparently do not age, but grow bigger and more fertile with the passage of time. (The record weight for a lobster was 44 lbs.) Mitteldorf describes some species of long-lived shellfish that are almost nothing but feeding and egg-laying machines, cranking out a million eggs daily.
But humans and most animals do age. Animals in the wild have a greater chance of death from predators and infections the older they are. Why hasn’t evolution put a stop to this?
One older idea, that of Peter Medawar, is that the force of natural selection declines with age. If an organism has aged and then dies, any genes that contributed to aging and death have already been passed to its offspring. The idea is that some genes that may cause aging are also necessary for growth and reproduction. Therefore natural selection is unable to eliminate the genes for aging.
Medawar’s idea led to the three main modern theories of aging.
Mutation Accumulation: Genetic mutations are always present in a population; in other contexts, this is known as genetic load. If a mutation is not severe enough to cause death, but causes only, say, a 1% decreased level of fitness, then these genes can stick around in a population for a long time. Essentially, natural selection has not had enough time to get rid of them. An example might be the ApoE4 gene, which raises the risk of dementia and heart disease.
But even a 1% difference in fitness is, as Mitteldorf says, “far from being invisible to natural selection”. Aging animals do not die of senescence usually, but they die at a much greater rate from disease and predators than younger animals. In some arctic species, 60% of deaths in the wild can be attributed to aging. Natural selection should be capable of eliminating the genes that cause this huge death toll, and to be able to do it quickly.
Antagonistic Pleiotropy: Some, maybe most, genes have multiple functions, and this theory says that genes with important functions in youth cannot be weeded out when they cause aging. An example of this might be the hormone IGF-1, which is involved in both growth and aging. Mice without it die shortly after birth — but high levels in older people are associated with cancer and higher mortality.
Mitteldorf describes the work of Michael Rose, who bred fruit flies for longevity in order to see what would happen to fertility. In theory, if he selected long-lived flies and bred them for longevity, their fertility should decrease, given antagonistic pleiotropy. But that’s not what happened; their fertility went up. So there seems no reason that nature can’t separate the function of fertility from aging.
Disposable Soma: Resources, usually in the form of food energy, are always in short supply, so this theory says, so that organisms must allocate these resources to different needs. Damage repair at the cellular level is one of those needs and is an important component of aging, since if the body can repair all of its damage, aging will not occur. So if resources are lacking, the organism allocates them preferentially to growth and reproduction, and essentially allows itself to age.
The huge counter to this theory is calorie restriction, the most robust life-extending intervention in lab animals. When they are literally starving, animals can live 50% longer than normally fed animals. If resource scarcity were causing aging, we could expect to see the opposite. If you ate more, you would live longer; but such is manifestly not the case. Eat more, die younger — and this holds true for virtually every species of organism which has been put to the test.
Same is true for exercise: if damage and repair are crucial for aging, exercise would make you age faster. Exercise causes damage — yet it makes animals, including humans, live longer.
Both calorie restriction and exercise are examples of hormesis, in which the application of a stress or toxin causes better health and longer life. The organism doesn’t just repair the damage, but becomes stronger and healthier than before.
Hormesis is central to Mitteldorf’s theory of aging. As he says, it looks as if the organism already has potent anti-aging capabilities that, in normal, “easy” times, it does not use. The organism is fully able to slow aging, when the conditions are right.
Aging is not damage that the body can’t control or that natural selection can’t abolish. It isn’t due to lack of resources or pleitropic genes. No.
Aging is programmed.
The theory of programmed aging clashes directly with the neo-Darwinian theory of evolution, which is the theory that represents current thinking in biology.
Neo-Darwinian theory states that natural selection takes place at the level of the gene, and only benefits individuals carrying that gene.
Mitteldorf’s theory of programmed aging relies on group selection, a notion that most evolutionary scientists say cannot exist.
Hence my description of Mitteldorf’s theory as radical, since it takes on the entire neo-Darwinian synthesis, and the scientists that back it.
In this light, it’s of more than passing interest that Mitteldorf’s mentor has been another proponent of group selection, David Sloan Wilson, the author of the masterful book Darwin’s Cathedral: Evolution, Religion, and the Nature of Society.
The programmed theory of aging sees aging as a “suicide program”, one that is of no benefit to the individual but which is of great benefit to the group. The organism dials up genes that cause inflammation and other forms of damage, leading to aging and death. Aging is a deliberate effort on the part of the organism, not something it tries to avoid.
Why would organisms do this? The benefit to the group would have to be a very powerful one in order to override the harm to the individual. And indeed it is, according to Mitteldorf.
Organisms age in order to avoid extinction.
In any successful group of organisms, it seems easily possible for the group to overshoot its environment and to succumb to famine or other causes.
All animals are predators in some way or other, depending on other life forms for sustenance, and if the animals are too successful, they risk famine or epidemics and subsequent extinction of the entire group.
Aging is the organisms’ way of buffering the population. In good times, with plentiful food, organisms age and some of them die, thus keeping the group within its environmental limits and in tune with its ecology. The group thrives.
In bad times, with fewer available resources, aging slows. The species does not want every member to die at once, of famine or some other cause. It wants to avoid extinction, an event which means the demise of every gene carried by the species. When the crisis is over, aging resumes.
Mitteldorf supplies abundant evidence for his theory, and it makes for fascinating reading. While reading it, I thought of a few objections, which wasn’t easy, as the author is convincing. Note that I am not an evolutionary biologist.
Aging seems too messy a process to be a “suicide program”. If you think of all the ways that aging causes damage, illness, and death, how could multiple sources of these things arise? One gene that caused death would be a lot simpler, and the fact that aging apparently has multiple genetic roots makes one wonder how it could arise by natural selection.
Admittedly, this objection is probably more a matter of taste than of empirical backing.
Another objection is that the mere passage of time seems involved in some aspects of aging, for example, in the accumulation of iron or exposure to antigens.
Iron seems a good example of pleiotropic effects: it’s necessary for growth and reproduction, but causes aging. Furthermore, natural selection might be unable to eliminate its effects on aging. Women with higher iron are more fertile, which might swamp the effect of natural selection on iron causing aging after a person has already had children.
Antigen exposure comes from infectious agents, and is a primary cause of inflammation in aging. The longer we live, the more antigens we’re exposed to, and in fact those exposed to more diseases die younger, i.e. they age faster. But perhaps the organism can’t dial down inflammation, since we need it to fight off pathogens.
Cracking the Aging Code is the best book I’ve read this year, and should be required reading for anyone interested in aging or indeed evolution and biology. Mitteldorf skillfully wends his way through evolutionary theory, its history, and the biology of aging — he even knows his chops when it comes to field biology and ecology.
At the end of the book, he discusses the prospects for anti-aging research as well as what he believes are the best means of slowing aging that we have right now.
His ideas about slowing aging are, I’m happy to say, very much in tune with what I’ve expounded on this site: exercise, intermittent fasting, supplements like berberine and curcumin, aspirin, and more. (He should have mentioned iron.) On the horizon are technical developments like telomerase therapy, which hold great promise in getting to the root mechanisms of aging.