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.

Saturday, July 2, 2011

Aspen Ideas Festival - Highlights

Liaquat Ahamed’s talk on "The Lords of Finance" began with a tour of some colorful characters of the early 20th Century world of banking, but quickly morphed into an insightful comparison of the 1929 stock market crash with more recent woes. The two bubbles show many similarities (e.g., overly easy credit leading to overborrowing) and some differences (an imminent sense of doom in the 1920s, versus financial hubris in the run up to 2008-2009).

But the main contrast is between how the US government handled the banking crisis once the bubble burst. In the aftermath of 1929, banks were allowed to fail, budget deficits were avoided, and interest rates were allowed to rise. Say what you like about Paulson, Geithner and Bernanke, but they did not repeat the mistakes of the 1930s. The stock market may have fallen a comparable 50% or so, but the recent crash was not accompanied by 25% unemployment. Ahamed attributes the avoidance of this outcome to the well-known bank bailouts, stimulus packages and interest rates controls, and it’s hard to disagree.

At the end of question time, Ahamed introduced the sobering idea that we are about to enter a ‘lost decade.’ In other words, growth and stability will have to give way to significant changes in both our economic and social arrangements. If found it easy to believe that this is so, and that the 2010s could join the 1930s and the 1970s in history as a time of more or less painful adjustment.

The full title of this session with Thomas Friedman (and his latest book) is “That Used To Be Us: How America Lost Its Way in the World It Invented and How We Come Back.” The leading phrase is taken from a speech by President Obama concerning economic progress in China (better rail system and the fastest supercomputer). The interview was conducted by Walter Isaacson of president and CEO of The Aspen Institute.

Friedman began by talking about the American Dream, and how “its future is now in play.” Americans can no longer assume that each generation will be better off than the one before, while our deteriorating infrastructure suggests things may actually get worse. He sees the possibility of a slow decline, and worries that Americans are getting used to second best.

According to Friedman, America’s past success was rooted in a public/private partnership with sensible policies around education, immigration, infrastructure, risk/capital management, and scientific research. Each of these five pillars now seems to be crumbling. Further, the US has “declared war on math and physics” by turning a blind eye to financial legerdemain and climate change. Markets and Mother Nature will correct us, if we don’t correct ourselves, and it won’t be pretty.

Robert Rubin, co-chairman of the Council on Foreign Relations and formerly of the Clinton administration, was interviewed by Chrystia Freeland of Thomson Reuters. Rubin stated that the US is at a ‘historic crossroads’ and that the ultimate challenge is political, not technical. Washington needs to address the debt crisis, finance public investment, and reform education and healthcare, but ideology and opinion are getting in the way of facts and analysis, and the media isn’t helping much.

At question time, Rubin said he was ‘really worried’ about the current impasse over the debt ceiling, and thought the situation was ‘horrendously risky.’ Making the debate about debt a debate solely about spending, is completely wrong, in his view. If the deficit is greater than discretionary spending, how can you cut your way to a balanced budget? The issues have not been framed properly, and there is no sensible discussion. I find it hard to disagree.

Like Tom Friedland, Robert Rubin ended by saying that he was optimistic. Both cited the basic strengths of the American people as the source of their optimism, despite having decried a certain level of ignorance in the electorate. One wonders if polarization is going away any time soon, given the ‘echo chamber’ effect of both traditional and social media, whereby people’s selection, sharing, and curation habits tend to reinforce their own deeply held beliefs.

More reviews can be found at the AIF blog and the Thomson Reuters blog.