Monday, July 4, 2011

Can Aging Be Reversed?

Jeanne Calment (1875-1997) lived 122 years in Arles, France, and died as the oldest documented person. Reporters would often ask her to what she attributed her surprising health and longevity, and her answers varied. She smoked (probably lightly) until she was over 100.

Can aging be slowed, arrested or reversed? This was the fascinating topic addressed by Dr. Thomas Rando of Stanford University at the Aspen Ideas Festival on Sunday. In a highly entertaining talk, he gave us reason to believe that there could be affirmative answers to each of these questions.

Aging versus Longevity

First, some distinctions. Aging is a process, which is not really measurable. Right now, we do not have a biomarker that tells us how old or aged a cell is. Consequently, we cannot measure how fast or slow someone is aging by looking at their cells or tissues.

Longevity, on the other hand, is eminently measurable, since it is simply elapsed time. Human life expectancy at any one time is defined at the age at which 50% of people die. The 1970 curve for life expectancy in the US tells us that 50% of people born in 1900 die at age 70. This curve is convex, unlike the curve for animals in the wild, which would be concave. In other words, most animals in the wild die earlier, with a long tail of survivors, while most humans survive with a more gradual falling off.

Life expectancy improved dramatically in the 20th Century. The 1900 curve exhibits a life expectancy of about 45 years, in large part due to a drop in infant mortality. The 2010 curve shows 80 years, as health gains continue into the 21st Century.

The Genetics of Lifespan

It is remarkable that there is a 100,000-fold difference in longevity between the shortest- and the longest-lived species. Mayflies live for less than a day, while a giant tortoise can live 200 years. There is also a slightly odd relationship between size and longevity. Larger species tend to live longer, yet within a species, smaller subspecies tend to live longer, e.g., consider different breeds of dog.

Furthermore, studies of model organisms (such as flies, worms, and mice) in laboratories have shown that mutation in a single gene can extend life. So one might ask: why do sexually mature individuals begin to age almost immediately? Why don’t they simply maintain themselves at a prime level of health? And what evolutionary processes are involved with aging?

Slowing or arresting aging

With regard to slowing down the aging process, we know that lab animals live longer if they are given fewer calories, but get adequate nutrition. The Caloric Restriction Society advocates this for humans, although there is as yet no scientific proof that such a regime is effective. Caloric reduction at levels that make a difference will increase feelings of hunger and cold.

The arresting of aging has been observed in certain animals that assume a state of suspended animation when conditions are unfavorable. E.g., worms go into what is called a Dauer state, like hibernation, when the environment is challenging, emerging later without have expended lifespan in the process. 2000-year-old seeds have been found at excavations and subsequently been coaxed into supporting plant growth.

As with caloric reduction, hibernation is not a very attractive option for humans in the normal run of things. (Space flight and sitting out a few centuries of radioactive contamination suggest themselves as appropriate circumstances for doing this.) Meanwhile, pharmaceutical research is looking to understand the effective mechanisms behind caloric reduction and find a way to deliver the benefits in a pill.

Reversing aging

Skeletal muscle is apparently a good place to start when looking at the effects of aging. Young muscle makes new tissue in response to injury, but with age there is atrophy of individual fibers and a general loss of condition. Consequently there is impaired regenerative myogenesis, i.e., less striation and increased tissue fibrosis (scarring) in healing.

The question is: why don’t older people heal? They haven’t run out of stem cells. It’s as if their stem cells are ‘asleep’ and don’t ‘wake up’ when needed. Experiments have shown that stem cells can be activated if the signaling pathway is enhanced by additional molecules.

In a key experiment, known as parabiosis, mice are paired surgically, literally joined together so that they form a shared circulatory system. If you have both young and old mice, you can join like mice together (i.e., young+young and old+old) which is called isochronic parabiosis, or you can join unlike mice (i.e., young+old) which is heterochronic. You leave them together for months and look at re-striation in response to injury in paired mice.

The sort story is that isochronic pairs show no change in their ability to heal. The young do well and the old do less well. But the heterochronic pairs do well, as if the young half of the pair has somehow reset the old. This result holds good for every kind of tissue that has been looked at so far.

Leaving aside the grisly possibility of yoking young and old humans together, can the aging clock we reset by some other means? Obviously, cells can be reset. For example, fertilization of an egg resets the clock by making old cells young again, and a similar effect is seen in cloning. This kind of cell ‘reprogramming’ is usually accompanied by dedifferentiation, i.e., differentiated sperm and egg cells become undifferentiated again to an earlier stage of development. Yet, in the parabiosis experiment, exposing old cells to a younger environment ‘rejuvenates’ them without dedifferentiation.


This research is aimed primarily at healing older people heal, rather than extending their lives. Nevertheless, the results are suggestive of means by which aging could be reversed. One wonders if some combination of slowing and reversing could indeed extend life, should pharmacological means become available.

There were very many questions after this talk, but the main takeaway for me was the caution that Americans risk losing life expectancy in the current obesity epidemic. Could this generation really be the first to lose ground instead of gain? That would be a strange biological parallel to the current dwindling of the American Dream.