Of Mice and Men

For middle-aged mice, these are the best of times. Scientists now understand genetic factors that lead to the development of disease, disability, and death—in mice. Most importantly, researchers have found ways to improve the “healthspan,” the period of disease- and disability-free life before death—in mice. The question is whether the approaches they are developing will be applicable to people, and the ethical implications if they are.

The basic ideas are spelled out in a trio of “viewpoint” articles published in JAMA last week. S. Jay Olshansky, writing from an epidemiologic perspective, observes that over the past century, dramatic gains in life expectancy have been accomplished by reducing in mortality of children and young adults. But once these gains have been made, the only remaining way to lengthen life expectancy is by extending the lives of people at the other end of the age spectrum. Medical science has therefore concentrated on tackling the diseases of old age, one by one. Unfortunately, as Barzilai et al comment in their essay, “efforts focused on preventing individual diseases will have limited net effect on population health because one disease will be exchanged for another.” We’re already seeing this phenomenon: as fewer people die of heart disease, they develop and die of Alzheimer’s instead. Far better would be to tackle the aging process itself. Targeting the underlying driver of all the chronic diseases at once could, in principle, prevent or at least delay those disorders.

So, what do we know about turning off biological aging? We know there’s a gene in mice with the euphonious name rps6kb1 and if it’s “knocked out” (molecular genetics speak for “inactivated”), female mice live longer, healthier lives. We know there’s another gene called Sirt6 (short for Sirtuin 6), which is present in multiple mammalian species including humans, and if it is “overexpressed” (genetics speak for “turned on”) in male mice, they live longer. We also know that all creatures including people have “senescent cells,” cells that, old cells that start releasing all kinds of chemicals. When an individual has more than some threshold number of such cells, it develops chronic diseases, frailty, and is at high risk of dying. When the senescent cells of a mouse are destroyed, the mouse lives longer and without a long period of deterioration before death.

And what progress has been made in identifying drugs that achieve these goals in mice? And what about in people? Reportedly, the Interventions Testing Program, funded by the National Institute on Aging, has examined 26 “candidate drugs” for their effects on mice. They have identified 6, including the anti-inflammatory drug, aspirin, the anti-diabetes drug, acarbose, the immunosuppressive drug, rapamycin, and the estrogen, 17a-estradiol, as effective in some mice. Intervening in mice of an age equivalent to 70 human years has “extended life by more than 20 years and increase[d] health span even more substantially.” Other studies have found that the drug dasatinib (related to the anti-cancer drug, Tarceva) has a powerful effect in destroying senescent cells. In mice that are the equivalent of 80 human years, treatment with dasatinib combined with quercetin (a plant chemical found in green tea, red wine, apples, and other foods) increases survival 36 percent without increasing disability before death.

We don’t know whether any of these chemicals work in humans. And we have no idea at all whether they will produce side effects, though we do know that earlier attempts to interfere with cell lifespan were associated with the development of cancer. This is not entirely surprising, as the essence of cancer is uncontrolled cell proliferation. So even the very upbeat article by Tchkonia and Kirkland, the third of the triad, ends on a cautionary note: “…Patients should be advised not to self-medicate with senolytic agents or other drugs that target fundamental aging processes in the expectation that conditions alleviated in mice will be alleviated in people.”

If, years from now, human studies indicate the drugs or others like them are effective, we will have to deal with the ethical implications of extending the “healthspan.” What will they cost? Will everyone have access to such medications? Will we create greater inequality within society? Between countries? Banning such research on the grounds that a ballooning of the elderly population is unsustainable is almost certainly going to be impossible—the lure of more disease-free life will be irresistible. But we can begin to think about the consequences of our brave new world.

Luck and Genes

My mother’s friend Lixie died last month. Eight months ago, her husband (my father) died. And just about exactly a year ago, my mother’s friend Walter died.

The three of them were all in their 90’s: Lixie died 6 weeks after turning 92; my father also died 6 weeks after turning 92; Walter died 6 weeks before he would have been 92. My mother, who still lives independently though she is not as vigorous as she was a few years ago, reached age 91 in December.

They had something else in common: all three were born in Germany or Austria in the 1920s and left thanks to the efforts of a group of Belgian Jewish women who sought to rescue Jewish children from an uncertain fate. The group of 93 children stayed in Brussels until the Germans invaded Belgium. They then made their way to unoccupied France, where they found refuge until 1942, when France no longer provided a safe haven for them. My parents escaped individually to Switzerland and eventually, well after the end of the war, made their way to the US. Lixie remained in hiding in France until the end of the war. Walter was one of the few teenagers to manage to immigrate to the US during the war. The story of the “Children of La Hille” is told by Walter in a book published shortly before his death; I tell parts of the story in my memoir about my parents, Once They Had a Country. 

Of the 93 children in the original group that made their way to Brussels, 82 survived the war.  And of those 82, many are living into their nineties. In addition to the four I mentioned above—my mother and the three who died within the past year—I know of another three who are alive and over ninety. There may be more. Surely this is more than one would expect in a cohort of people born in Europe in the mid-1920s.

Curious, I looked at what is known about the longevity of Jews who survived the trauma of 1939-1945 in Europe. And what I found was very interesting indeed. An article called Against All Odds found that survivors of “genocidal trauma” during World War II were likely to live longer than a comparable group not exposed to the same trauma.

The study looked at Israelis born in Poland who were between 4 and 20 years of age in 1939. They compared those who came to Israel before 1939 with those who arrived between 1945 and 1950, defining as "Holocaust survivors" anyone who spent the war years in Europe, regardless of whether they were in a concentration camp, hiding in a convent, or on the run. The justification for this broad definition is that in all cases, their lives were in extreme jeopardy. 

The authors of the study examined at the experience of 41,454 Holocaust survivors and 13,766 controls. What they found was that Holocaust survivors were on average likely to live 6.5 months longer than those who were not in Europe during World War II. This despite ample prior evidence that Jews who spent some or all of the war years in Europe had a high rate of post-traumatic stress disorder in later life.

What does this mean? It’s not certain what it means, but one possibility is that whatever factors led this high risk group to survive under adversity also led them to survive into old age. And since there’s no reason to believe that just because you were lucky once, you’ll be lucky again, I suspect that a key factor is genes. Those Jewish children who managed to survive the war, including the Children of La Hille (who, because of the assistance they received, faced better odds than their counterparts who were not part of this group), were better equipped to endure. That capacity continued to help them for the remainder of their lives.

This explanation is, of course, entirely speculative. It’s conceivable that the longevity of the Children of La Hille is simply due to chance. But I am telling this story because it is a reminder that much of the experience of aging is shaped to a large extent by factors beyond our control—by luck and genes. 

This doesn’t mean we shouldn’t try to improve our chances of survival by preventing whatever part of illness and disability is preventable. It doesn’t mean we shouldn’t do what we can by exercising and eating a good diet, by avoiding drugs and alcohol, and by controlling conditions such as high blood pressure. But let’s have the humility to remember that we have only a modest ability to determine our fate. All those who, unlike the Children of La Hille, don't have good luck and good genes, should nonetheless have access to the medical care, housing, and social services that allow them to have as good a quality of life as possible, however many years they live.

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Food for Thought

The global anti-aging industry is valued at over $195 billion and will grow to $275 billion by 2020. But the assessment of the effectiveness of its products made by three leading scientists in 2002 has not changed. And what they said is that “no currently marketed intervention—none—has yet been proved to slow, stop, or reverse human aging, and some can be downright dangerous.” They then go on to say that "the public is bombarded by hype and lies." Or, as one of the triumvirate put it in a recent NY Times article, "as soon as the scientists publish any glimmer of hope, the hucksters jump in and start selling."  

In light of this reality, my internal alarms started going off when I saw the headline in last week’s NY Times, “My Dinner with Longevity Expert Dan Buettner (No Kale Required).” Granted, the article was in the “Fashion and Style” section of the Times, not the health section and not the science section. Now don't get me wrong: diet and exercise do matter: eating well and remaining active decrease the chance of developing disease and disability. Not only that, but modifying what you eat in the hope that it will promote longevity is far more benign than purchasing expensive supplements or herbal remedies that have no proven efficacy and are quite possibly harmful. But still—is Dan Buettner really a “guru of the golden years” who has spent “the last 10 year unlocking the mysteries of longevity?” He traveled to five of the places on the globe with the longest lived people: Icaria, Sardinia, Okinawa, the Nicoya Seaside of Costa Rica, and Loma Linda, California and wrote up his interviews. He was not funded by the NIH as the report would have us believe: he was funded by National Geographic to report on peoples who were being studied by teams of scientists funded by NIH. He did write a cover story for National Geographic in 2005 about the people he met on his travels and how they lived, particularly how they ate. And he converted his article into a book, The Blue Zone Solution, published by National Geographic Press this past spring.

            National Geographic ran a cover story about diet and longevity once before. The magazine reported in 1973 on Dr. Alexander Leaf’s travels to the Caucasus where he studied people who ostensibly were 120 years old. It would turn out that these human marvels were actually only in their nineties, at best. In fact, according to Dr. Tom Perls, head of the New England Centenarian Study, 98% of claims of age over 115 are false, as are 65% of claims to be 110. 

            I’m not sure why the NY Times ran this story. But I was sufficiently intrigued to look into what we do know about diet and longevity.

         For starters, it’s important to distinguish between people who live a long time and people who live a very long time. What is pretty clear is that the variability in life span for people in the first category can be explained by a mixture of environmental and genetic factors. We can’t control who our parents were, but we can control, to some extent, our environment. So what we eat is one of the things that does matter, at least as far as increasing our chances of making it into our eighties is concerned. Exceptional longevity—centenarians and “super-centenarians” (people over age 110) are a different story. For this group, it’s all about genetics. 

            But can we say much more than what was concluded from the Whitehall study, a longitudinal study of aging in Canada that found the 4 behaviors that increased the chances of being in good health after age 60 are regular physical activity, eating fruits and vegetables daily, drinking alcohol in moderation, and not smoking? What do we learn by looking at  the dietary habits of people in Buettner’s “blue zones” of above average longevity?  

          For several decades, geriatrician Bradley Willcox and his twin brother, anthropologist Craig Willcox, have been leaders of the Okinawan Centenarian Study. They have identified a variety of factors which, together, seem to account for the long lives of Okinawans. It’s not just about diet. It’s also about living in a culture that values group activities and fosters a strong sense of community. It’s about living in a slower paced, low pressure world where people get around by bicycle. But yes, it’s also about diet. And while each of the longevity hot spots of the world has its own culinary specialties, they all have much in common. They all feature a high intake of unrefined carbohydrates and a moderate intake of protein, mainly from fish and legumes. Their foods have a low glycemic load, include a goodly number of anti-oxidants, and are low in saturated fats.

         How much of a role diet plays in the 30-50% of longevity that is due to environmental factors is unclear. Also unclear is whether diet interacts with social factors to make a difference. It’s conceivable that what you eat matters, but it matters a good deal more if you also live in an all-embracing community. At least as interesting as the Sardinians and the Costa Ricans are the Seventh Day Adventists of Loma Linda (whom, to be fair, Buettner visited as well). The people of Loma Linda are physically active and tend to be vegetarians. They are also very involved in their community and deeply committed to their religious faith. So maybe, just maybe, it’s not only what we eat that determines how long we live. Just some food for thought.