Benjamin Franklin wrote in 1789, “The only things certain in life are death and taxes.” Well, for the last couple of years General Electric has shown that it is possible to make billions and pay no taxes. And some recent startling advances in aging research suggest that Ben might have been wrong on both counts.
A unifying theory of aging is beginning to emerge. It explains many previous and apparently disjointed observations through a common mechanism. Let’s call it the Continued Accumulation of Crud with Aging, or CACA model.
It is no surprise that unwanted junk accumulates in cells with age. Some organelles, such as mitochondria, can break down, and sit around useless. Protein aggregates, or clumps, can form with time.
Cells have developed a sophisticated mechanism to eliminate unwanted material. It is referred to as autophagy, or self eating. The process is pretty amazing, and still not completely understood. First cells need to be able to recognize the things to eliminate. Then they engulf them with a membranous structure called an autophagosome, which then fuses with a stomach like structure called a lysosome, which breaks things down to small subunits that can be re-used by the cell.
It turns out that many things that activate autophagy can prolong lives.
Caloric restriction, or simply eating less without malnutrition, has been shown to significantly extend lifespan in a wide variety of model organisms, including mice, rats, fruit flies and dogs (http://en.wikipedia.org/wiki/Calorie_restriction). And as might be expected, caloric restriction promotes autophagy. When cells aren’t given enough to eat they begin to self-cannibalize, or eat themselves.
It is also interesting to note that an unbiased screen for genes involved in aging in yeast found many genes that function in autophagy. It turned out that inactivation of these same genes in fruit flies also reduced life span, resulting in the accumulation of dysfunctional mitochondria, muscle degeneration and heart malfunction.
It has also been shown that the drug rapamycin can dramatically extend the life span of yeast, invertebrates, and mice (http://www.nytimes.com/2009/07/09/health/research/09aging.html). Although rapamycin has many effects, and the best advice at present is please don’t try this at home, one of the key functions of this drug is to activate autophagy.
Resveratol, which is found in wine, has been proposed as a partial explanation of the puzzling observation that the French eat a high fat diet yet have relatively little heart disease (http://topics.nytimes.com/topics/reference/timestopics/subjects/r/resveratrol/index.html). It turns out that resveratol turns on the Sirt1 gene, which activates autophagy.
It is also interesting to consider the correlation between body size and longevity (see The Comparative Biology of Aging, by Norman S. Wolf). In general smaller animals have shorter lives than larger ones, with mice for example living only a couple of years, while people, horses and elephants can live for decades. But within a species there is often an inverse relationship, with smaller dogs for example living on average much longer than big dogs. The bigger dogs are known to have elevated growth hormone and insulin like growth factor signaling, which inhibit autophagy.
An important recent advance came from the study of people with Progeria, who show extremely rapid aging. Although apparently normal at birth they typically present symptoms before the age of two. They grow slowly, lose their hair, have fragile bones and thickened skin, and usually die in their teens from heart attack or stroke. The disease is caused by a mutation that results in the accumulation of an abnormal protein called progerin, which results in time in their cells showing nuclear blebbing, a very abnormal and sick structure.
Francis Collins, the Director of the National Institutes of Health, and his colleagues recently published an important study of the effects of rapamycin on Progeria patient cells grown in culture. They showed that rapamycin can cure the cells of nuclear blebbing by promoting the clearance of progerin through autophagy (Science Translational Medicine, June 29, 2011). To quote their paper, “the results reported herein support rapamycin as a potential treatment for children with Progeria.”
And, if we can learn how to effectively treat the accelerated aging of Progeria it raises the possibility that in time we might be able to treat the normal aging process that we are all currently experiencing. Of course the CACA model does not explain all of aging. There are additional forces at work. But ever increasing evidence argues that it is a very important component of the aging process.
But should we cure aging, even if we could?? Some would argue that aging and death are good things. After all, don’t we have too may people already? But who on earth would refuse an offer of an additional ten, or twenty, or even fifty years of healthy life?