Scientific efforts to extend lifespan are progressing on several fronts. A short-lived species can evolve into a long-lived one, and researchers are keen to find out how (S10). Studies in other species have already shown that a severely restricted diet can add years of healthy living (S18). Diet affects ageing in humans too — how our food influences our gut microbes, and how they in turn affect our health and longevity, is under investigation (S14). Another line of enquiry focuses on harnessing the regenerative powers of stem cells (S12).Progress! So, having a long-standing interest in this subject, we thought we'd better check this out. We read the papers, and, alas, it turns out that the Fountain of Youth has not yet been found. Even with the latest technology -- stem cells, fMRI, genomics, etc -- basic questions about aging remain unanswered.
For example, what happens to the brain as it ages? In the piece, "Cognition: The brain's decline," Alison Abbott writes that it's surprising how little is known about healthy aging of the brain.
Researchers still don't understand the mechanisms underlying the decline or the order of events. They can't explain why some people manage to stay cogent and alert well into their 80s, whereas others become slow-witted and forgetful in their 60s. They don't even know whether Alzheimer's disease is an abnormal pathological condition or simply an acceleration of normal ageing. And no one knows of any drugs that can help those who lose cognitive function as they age, or whether brain training programmes really help.What is healthy aging anyway? Aging researcher Eva Kahana says that her study on aging in a Florida retirement community shows that healthy aging happens when people move away from their families and into retirement homes in Florida. Against all expectations. Hmm....could there be a reason that reflects the kinds of study design issues we write often about? Well of course, unhealthy people are a lot less likely to move away from their families into retirement homes in Florida.
Stem cells would seem to hold the key to un-aging, but stem cells in older people don't behave the way they do in younger people because, well, they're older, and figuring out how to enlist them in the quest to rejuvenate tissues and organs is a challenge. And, might have unintended consequences, writes Peter Wehrwein.
Technology can be harnessed, however, and is being used increasingly to help elderly people with limited mobility or memory issues to retain some or full independence. Sensors, beepers and so forth can call for help as needed, or remind people to take medication and so forth. But then, we're very good at making technological advances, and figuring out how to use them, so this isn't a surprise. And it is good news.
"Scientists are searching for a genetic blueprint that will enable humans to stay healthy and vital well into their old age," writes Michael Eisenstein. The idea is that extremely old people are genetically protected from diseases of aging, such as cancer or cardiovascular disease, until well into old age. So, researchers are looking for genes for "compression of morbidity" in "longevity genotypes." This means genomewide association studies in centenarians, by and large.
It's hard to imagine how genes 'for' old age evolved, since natural selection doesn't have any way to act on traits that are post-reproductive, but researchers suggest that perhaps they arose and then hung around in long-lived families as "family heirlooms," without the "evolutionary momentum" to spread. If so, they would presumably be fairly recent, since living past 100 is largely a recent invention. A more likely suggestion is that, if there are in fact genes that contribute to long life, they have some other function as well.
Sarah Deweerdt suggests ("Comparative Biology: Looking for a master switch") that by using short-lived animals like C. elegans and mice as model study subjects researchers are studying exactly the wrong species. Instead it might be more fruitful to look at long-lived animals, to try to figure out why they live so long. If there is in fact a single answer, or 'master switch.'
Single gene mutations apparently can have an effect on mouse longevity, extending life spans significantly as described in the piece by Katherine Bourzac ("Interventions: Live long and prosper"). But, this doesn't necessarily mean that single genes are responsible for the long lives of elephants or Galapagos turtles, or human centenarians. Traits on the extremes of normal distributions are often found to have different genetic bases than the traits in the middle. Intelligence and stature are examples of traits that work this way. Single genes associated with longevity may explain it in the extremes, but may not explain the bulk of the population of, say, healthy octogenarians.
And then there's the idea that calorie deprivation leads to longer lives, an idea for which the data seem to be equivocal. Rhesus monkeys living on starvation diets for 25 years did not live longer than those on more calories (which we blogged about here). They may have more resistance to disease, however.
Finally, researchers are studying the microbiome of elderly people and finding it to be different from that of younger subjects ("Microbiome: Cultural differences"). And the gut of sick people is populated by different bacteria than that of healthy people. Whether the different microbiome is a cause or an effect of aging, or illness, is an unanswered question.
One size fits all, again? Not!
There have been many decades now of aging research, and Ken has done his share of it (years ago). The fervor for a simple explanation fits very well with our current era's belief in and hope for point-causation, something we can make a pill for, or engineer out of our genomes, etc. Point causation is something conceptually derived from classical physics in a way. And we have in biomedical history, decades when everything, so to speak, was caused by infection. This all reinforced the materialist or 'physicalist' assumption that simple laws must account for everything, and in life that 'physical' must mean genes.
Whetting this feeling, besides all the careerist and other such motives, was a generally simple relationship among mammals between body size and length of life. There were tons of misapplied evolutionary arguments and billions in grant funds wasted chasing down what some of us said clearly at the time were naive beliefs based on this, and the more serious underlying questions were rather neglected.
Still, the idea of a body-size determinant of how long an animal lives is appealing to one searching for one cause. That's why telomeres and energy turnover per pound of body weight (with associated damage) and other magic answers had such appeal. One cause, if we can only find it, must explain when we die.
That's strange, and again some of us were pointing this out long ago, because why we die shows no such thing. We die of a diversity of causes that basically share no simple physiological or genetic relationship. Cancer involves many mutations accumulating among cells during life; heart attacks from arteries clogging slowly up, diabetes from too much body weight or gradual resistance to insulin; stroke from arteries gradually hardening or weakening until one bursts. There is no single physiological process that seems able to account for this. Yet, the same disorders strike humans, dogs, horses, and mice at similar ages relative to their typical lifespan. There is this total apparent difference in process, but a species, and perhaps brain or body size calibration (other branches of life have their own 'calibrations' and they don't follow the same pattern as mammals, though trees and frogs and sea urchins have their own general aging--see our recent 'immortal' jellyfish post for an interesting take on all of this).
But maybe there is 'a' way, after all...
One way (in principle) may account for it. This is based on the observation that cells accumulate all sorts of damage. Some of it includes mutation, but not all. Some of it can be repaired but not all. As cells divide and then cook along and then divide during life, there can be an increasingly damaged overall state for an increasing fraction of cells in a particular organ and, because each organ is physiologically different, among organs. A paper in the current issue of the journal BioEssays presents some ideas of this kind in a newer, integrated way than was possible in the past.
When enough damage--whatever the specifics be--strikes enough cells, or strikes one cell badly enough (to start a cancer), then the organism, and not just its cell, is in trouble. Call the preacher and schedule the service!
The interesting thing about this, which is again something Ken wrote about as long ago as the 1980s when much less was known about the cellular details, is that very different processes can accumulate damage in a way that increases similarly with age. The rate of death from different causes may be hugely different in absolute terms (say, one in a thousand per year to one in ten thousand, etc., for different causes of death). But they increase in a curve (called the 'hazard function') that has the same accelerating 'shape' when you graph it.
You are at risk from all of these causes every year, and every year the chance that you escape all of them to live another year diminishes. As a result, we need not have a single cause that turns us off at some typical age.
In a general way, this can explain how we can have a characteristic curve in our risk of death with age, even if each person goes by his or her own cause. There need not be one underlying bullet with our name on it. But this leaves open an interesting question, and in a way returns us to the reason that thoughtful people, at least, thought that aging might have a unitary cause: Why do these accelerating processes accelerate at different rates in different species, in a way that leads to the correlation of length of life with body or brain size?
For example, a problem noted in a general way in the early 80s or before, by Richard Peto the British epidemiologist, but that we can put more precisely today is this: Mice have similar cell types and similar genes and similar diseases and these even have similar rates of risk acceleration with age. But if the same kind of accumulating damage is causing the same kind of result, why would a particular type of cancer hit a mouse more than 100 times earlier than it does a human? If this reflects some underlying common cause, how can that affect so many different cell types so differently.
One can suggest an answer, but it's premature and this is not the place to air it....
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(Hefty contribution to this post from Ken.)
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