We’re all going to die, but we don’t like to think about it. I’ll reach the proverbial threescore years and ten next month, so I’ve been thinking more about it, wishing I knew some reliable way to ensure that I would live many more years and remain fully functional until I suddenly collapsed like the Deacon’s wonderful one-hoss shay. There are myriad “longevity clinics” and “anti-aging” formulas, and every centenarian has an explanation that is the direct opposite of some other centenarian’s explanation. But what does the scientific evidence say? In his new book Spring Chicken: Stay Young Forever (Or Die Trying), Bill Gifford has done us a great service by investigating the latest scientific evidence about aging and presenting his findings in an engaging narrative form. He interviews some of the major players and introduces us to health fanatics who are convinced they can prolong their lives by doing things like monitoring their own blood cholesterol levels on a weekly basis, exercising obsessively, severely restricting their calorie intake, fasting intermittently, deliberately exposing themselves to stress like swimming in icy water, competing in extreme athletics, taking boatloads of hormones and supplements, experimenting on themselves with investigational drugs, and doing other questionable and sometimes bizarre things.
Are there limits to human life expectancy?
There is no documented case of anyone living longer than Jeanne Calment of France, who died at the age of 122. Jay Olshansky thinks biological forces limit how long we can live. Aubrey de Grey thinks some people alive today will live to be a thousand years old. Gifford explains the controversy and the reasoning behind both sides. Will we someday be able to re-engineer human biology to overcome the limits? The jury is still out.
How long do we really want people to live?
In Anthony Trollope’s 1882 novel The Fixed Period, a society votes to euthanize all citizens at age 68 to spare them undignified suffering and cut down on the state’s expenditures on unproductive people. One of the characters agrees that it is a good idea…until he approaches that age himself!
Physician Ezekiel Emanuel recently got a lot of attention with his article in The Atlantic saying he wanted to die at age 75 before disabilities impaired his quality of life.
If people lived longer, it would create problems for society like overpopulation and insufficient food. George W. Bush’s Council on Bioethics argued against aging research; Gifford says it concluded that it “would result in nothing more than vast numbers of unhappy old people hanging around, getting sicker and spending everyone else’s money and making grumpy remarks at holiday dinners.”
Not just long life: healthy aging
Most people would like to live as long as possible if their quality of life could be maintained. Even Jay Olshansky is optimistic that we are on the verge of a breakthrough about aging that will rival the discovery of penicillin, that will enable most people to delay the most debilitating diseases of aging, that will transform health care and even benefit the economy. Unfortunately, while we are waiting for that breakthrough, many of the people who are trying hardest to beat aging are really only making things worse for themselves.
What Gifford calls “the Fountain of Youthiness” has become a big business. Bioidentical estrogens, testosterone, human growth hormone (HGH), supplements, diets…the hype is endless. Longevity clinics and anti-aging remedies abound. Physicians like Dr. Oz and Andrew Weil and non-doctors like Suzanne Somers and Ray Kurzweil sell millions of popular books. Customers spend countless hard-earned dollars on unproven dietary supplements and devices. The American Academy of Anti-Aging Medicine has 20,000 members. But Olshansky says there is no such thing as “anti-aging medicine;” he says the secret to aging is that there is no secret.
The hype for HGH is based mainly on the misinterpretation of a single small study in The New England Journal of Medicine. In response to the hype, that journal later took the unusual step of stating in a strongly worded editorial that the study’s results were not sufficient to serve as a basis for treatment recommendations. In fact, HGH may accelerate the aging process. “Knockout” mice that lack growth hormone live longer and are much less likely to develop the diseases of aging.
Research on the causes of aging
Research looking for uniform markers of aging have found that there are none. The aging process is too varied, chaotic, and idiosyncratic; it’s different for every individual. Some 80-year-olds are barely mobile while others walk as fast as the average 40-year-old. Two random 20-year-olds will have much more in common than any two 70-year-olds. The aging trajectory seems to be largely determined by one’s health in middle age; the good news is that most key midlife risk factors are modifiable with lifestyle changes.
Many centenarians have “bad” genes but also have “preventive” genes that protect them from developing the diseases of old age. A gene that inhibits CETP (cholesterol ester transfer protein) is protective, but CETP-inhibitor drugs haven’t panned out. Centenarians have high levels of insulin-like growth factor (IGF-1), but their cells are resistant to it because of another gene variant. Most of us have the opposite of longevity genes: our DNA dearly wants to kill us.
What about evolution?
The diseases of aging are often called the diseases of modern civilization, but mummies from Egypt and Peru had arteriosclerosis, and humans may be hard-wired for heart disease. Can evolution explain the diseases of aging? They may impair the survival of the elderly individual, but there is little evolutionary advantage to surviving past the period of reproduction; the latter part of life becomes a sort of genetic garbage can full of irrelevant traits. In fact, some of the very genes that benefit us in youth may actually end up killing us later in life. For instance, the gene for hemochromatosis appears to have protected younger men from the bubonic plague in the Middle Ages, and it only causes harm later in life. Gifford quips, “Once we hit middle age, evolution pretty much takes its hands off the steering wheel and cracks open a beer.”
There are trade-offs between immediate survival and longevity. In the worm C. elegans, knocking out the IGF-1 gene doubles the lifespan, but when knockout worms were mixed with regular worms, the knockouts soon became extinct, because they reproduced ever-so-slightly later. This is mirrored in Ashkenazi Jews, who have fewer children later in life and live longer than other groups. Gifford says maybe having kids really does shorten your life!
Another hypothesis is that nature doesn’t need a possum that can live for 15 years if it is only likely to survive for 3 years in the wild. It is uneconomical for nature to invest more than is necessary to keep the body in decent shape for as long as it’s likely to live. Why pay for a Ferrari if a Chevrolet is plenty good enough to get you where you need to go?
In general, larger animals tend to live longer. (Dogs are an exception. Chihuahuas live longer than Great Danes, but this is an anomaly of manipulative breeding.) Humans are actually pretty long-lived, both relatively and absolutely. Only a few animals live longer, including the Galapagos tortoises and Ming, the Icelandic clam that researchers killed at the age of 507 (what an unfortunate clamity!). The longevity quotient is a measure of actual vs. size-predicted longevity. Only nineteen species have a higher LQ than humans: eighteen of them are bats, and the nineteenth is the naked mole rat. Long-lived species seem to have hardier cells; their cells resist toxic chemicals better in a dish in the lab.
Cells are programmed for death
Alexis Carrell, who invented cell culture, thought that cells could keep dividing forever; in his lab, they seemed to be immortal. (But his experiments couldn’t be replicated; his assistants had probably been introducing new cells into his cultures.) Hayflick overturned Carrell’s hypothesis when he discovered that cells predictably died after 40-60 divisions; this became known as the Hayflick limit. It was later explained on the basis of telomeres, repeating DNA sequences on the end of chromosomes that shorten every time the cell divides. The shorter the telomere, the shorter your life. I explained telomeres in a previous post. It seemed only logical that telomerase, the enzyme that repairs telomeres, ought to be a magic bullet for aging. So far that hasn’t panned out; mice given an experimental drug to increase telomerase didn’t live longer and they got more cancers. Anyway, some animals with very long telomeres and lots of telomerase actually have very short lives. It’s still not clear whether short telomeres actually cause aging and age-related diseases or whether increasing telomerase might increase the risk of cancer.
Another clue is interleukin-6 (IL-6), a cytokine that fights infections and heals wounds by inducing an inflammatory response. We produce more IL-6 as we age, and older people develop a low-grade inflammation that has been implicated in virtually every age-related disease. It gets more complicated. Old people still have a majority of cells that are still dividing, but they have a small percentage of cells that are senescent and that secrete a brew of inflammatory cytokines. It’s like a catch-22: cells go senescent instead of turning cancerous, but they create inflammation that helps make other cells cancerous. If we could figure out how to remove our senescent cells, we might be rejuvenated.
The worst senescent cells are found in fat tissue. Obesity is responsible for 14% of cancer deaths in men and 20% of cancer deaths in women. New evidence suggests that fat acts as a huge endocrine gland and may be the body’s most important organ for aging.
Stress, antioxidants, and naked mole rats
Gifford says much of what we think we know about stress is wrong. He discusses the health effects of psychological and biological stress, particularly oxidative stress. Antioxidants are another anti-aging candidate that hasn’t panned out. Antioxidant supplements do more harm than good. They diminish the benefits of exercise, prevent activation of the body’s own antioxidants, and interfere with the body’s repair mechanisms. Oxidative stress is beneficial, perhaps even essential to life. Increased levels of oxidative stress actually lengthen lifespan in worms. Bottom line: a little stress is good for us, and antioxidants are irrelevant to aging.
Naked mole rats, weird creatures that live underground and look like “a penis with fangs,” have high levels of oxidative damage, but they seem to undergo some kind of stress response that keeps them alive for decades. They don’t develop cancer, even when slathered with the highly potent carcinogen DBMA. It’s not even clear that they age. Their mortality rate doesn’t increase with age, and the females never go through menopause. The patterns of gene expression are the same in a four-year-old as in a twenty-year-old. They have achieved negligible senescence. But they are so different from humans that they can’t tell us anything about our own aging.
What might work?
Exercise may be the most effective “drug” for warding off many of the ills of aging. Studies show it has a multitude of benefits.
Severe calorie restriction has been shown to prolong life and improve health in a number of animals. Two studies in monkeys have produced contradictory results. A University of Wisconsin study found that calorie-restricted monkeys lived 30% longer; an NIH study found that the calorie-restricted monkey were not living longer, but their control monkeys were living as long as the Wisconsin calorie-restricted monkeys, probably because the University of Wisconsin monkeys were fed a diet comparable to a human junk food diet and the ones at the NIH were fed a healthier diet comparable to a Mediterranean diet. And while the NIH calorie-restricted monkeys didn’t live longer, they were healthier. It seems what you eat is as important as how much you eat.
Starvation has been shown to have surprising effects on health. We evolved in an environment where food was not constantly available, and our bodies are hard-wired to survive substantial periods of starvation. Intermittent fasting prolongs the life of yeast cells and improves the symptoms of asthma in humans. It increases the level of brain-derived neurotrophic factor and may help stave off degenerative conditions like Alzheimer’s and Parkinson’s. There is a cellular complex called TOR; when it is turned off, the cell goes into maintenance mode, recycling damaged proteins and cleaning up cellular junk; and fasting suppresses TOR. In one experiment, when patients fasted before chemotherapy the chemo was more effective and they had fewer side effects. Cancer cells have de-evolved and become specialized but less adaptable. “Cancer cells are dumb…when we fast, our healthy cells get smarter, or at least more adaptable to stress.”
Rapamycin inhibits TOR. In fact, TOR stands for “target of rapamycin”. In animal studies, rapamycin has been shown to extend not only lifespan but maximum lifespan, slow the formation of senescent cells, reverse cardiac aging, decrease inflammation, and strengthen bones. And it’s already available: the FDA approved it in 1999 for preventing rejection in transplant patients. But don’t get too excited yet. Gifford says:
The fact that you’ve read this far means, of course, that you are far too intelligent to take a powerful, possibly dangerous drug just because you read about it in a book written by an English major who has no business giving anyone medical advice.
Rapamycin has side effects. It’s a powerful immune suppressor that may impair response to pathogens. It increases insulin resistance, which would increase the risk of diabetes. An anti-aging drug for use in healthy people would have to be very safe, “safer than aspirin.” Since rapamycin works on basic pathways for normal cellular function, it is likely to have unpredictable unwanted effects.
Diet interacts with IGF-1 and TOR in ways that can be either good or bad. High carbohydrate diets are probably worse than high-fat diets, and high-protein diets may be equally bad.
Preventing Alzheimer’s? He cites a 2011 study showing that if 7 risk factors are addressed (diabetes, midlife obesity, midlife hypertension, smoking, depression, low educational level, and physical inactivity), fully half of all Alzheimer’s cases could be prevented. Another study found that people who had been physically fitter at age twenty-five remained more cognitively intact at age fifty.
Growth differentiation factor (GDF11). Supplying older mouse cells with the blood of young animals had a remarkable rejuvenating effect that was eventually attributed to GDF11. Researchers are looking at possible drug candidates that would activate GDF11 and possibly treat heart failure, muscle wasting and Alzheimer’s. It’s too soon to tell whether this will pan out.
In an appendix of “Things that might work” he lists:
- Resveratrol: an impressive array of lab results, but disappointing results in clinical trials.
- Alcohol/red wine: some evidence of benefit from moderate consumption. In one study the subjects who drank between 3 and 5 glasses a day were half as likely to die as the controls.
- Coffee: lowers the risk of diabetes and reduces overall mortality by 12% in people who drink 4 or 5 cups a day
- Curcumin: Beneficial, but has bioavailability issues and requires huge doses. Pharmaceutical research found that if you try to make it more absorbable, it becomes toxic.
- “Life Extension Mix”: More than 20 miracle nutrients; testing showed it significantly decreased lifespan in mice.
- Metformin: a diabetes drug that has a lot of other beneficial effects. Reduces the risk of heart disease and cancer in humans and extends lifespan in mice.
- Vitamin D: important for health, but supplements don’t seem to reduce overall mortality.
- Aspirin and ibuprofen: anti-inflammatory effect, some evidence of benefit for heart disease and longevity. One study found that ibuprofen was associated with a 44% lower risk of Alzheimer’s.
Gifford doesn’t recommend any of these as an anti-aging remedy.
Science is just beginning to understand aging and age-related diseases. The secret of aging is that there is no secret. As Gifford puts it:
Aging science has put together the edges of the puzzle…but we still don’t know whether the picture in the frame depicts a battle or a massacre. The secret to aging? Use it or lose it may be the best we can do for now.
Although he is a non-scientist, he has done an excellent job of explaining the pertinent scientific literature and putting it into perspective. He provides references for the scientist and makes the story interesting for the layman. What is really refreshing and what distinguishes his book from other books on the subject is that he stresses the uncertainty of our present knowledge and doesn’t try to tell readers what they should do to reach a ripe, healthy old age. I highly recommend the book.
This article was originally published in the Science-Based Medicine Blog.