Current Developments in the Amelioration of Aging

July 11, 2009

    Several significant developments have been announced during the past few days concerning the slowing and/or partial reversal of aging.
    One fact is worth noting. There is a tsunami of medical costs and problems approaching, as baby boomers age. The #1 risk factor for degenerative diseases is age. Any strategies for slowing the rate of aging or for combating age-related debilitation should delay and/or diminish all the degenerative diseases with one bullet... cancer, cardiovascular disease, Alzheimer's disease, Parkinson's disease, diabetes, etc. Furthermore, maintaining good health later in life tends to lead to scenarios in which decline and death take place rapidly, eliminating years of expensive medical care and patient misery. 
The Bottom Line:
    We're probably going to see increased emphasis on strategies for slowing aging, and for agents like resveratrol that lower risks for a spectrum of degenerative diseases with one pill. I have the impression that this concept is "sinking in" with policy makers.
    
(1) A news release on Friday is reporting that calorie restriction is showing the same kind and degree of slowing the rate of aging in rhesus monkeys that it has exhibited in mice.
    The back story here is that although calorie restriction has extended not only the average but also the maximum lifespan sizably in more than (short-lived) 200 species, there have been arguments that these kinds of gains wouldn't carry over to longer-lived species such as dogs, monkeys, and humans. This was a worrisome theme at the last (Fourth) Calorie Restriction Conference that I attended in Tucson in April, 2006. Cambridge University's Dr. Aubrey de Gray presented a paper entitled "The unfortunate influence of the weather on the rate of aging: Why human calorie restriction or its emulation may not add more than two or three years to the human lifespan." (This paper is no longer publicly available, but a summary of its "talking points" has been posted on the Calorie Restriction Society website.) Three other authors presented their own (mutually incompatible) expositions showing why calorie restriction wouldn't extend human life spans more than a year or two. I questioned their arguments because at least three out of four of them had to be wrong. Also, the arguments seemed to me to be easily refuted. Still, the final arbiters are the experimental results with large mammals, and especially, with primates.
    It's not easy to test longer-lived species because it takes so long to carry out the tests. One early Purina Dog Chow study (1987) of calorie restriction in 48 Labrador retrievers, 24 of which were put on a 25% calorie-restricted diet starting at 8 weeks, showed only an 11% increase in the maximum life span for the calorie-restricted dogs. (The median age of death for the calorie-restricted group was 15% greater than that of the control group.)
    However...
    There's one possibly-fatal flaw in the Purina study. At the time the study began--1987--it may not have been  known that when you put an animal on calorie restriction, you have to increase the average daily number of grams of protein it consumes even as you cut its overall calorie count by 40%... which means that the protein component of its diet must be increased by 50% or 60%, with the calorie reductions occurring in carbohydrates and fats. If the Purina researchers weren't aware of this, their calorie-restricted Labradors may have been malnourished.
    In any case, Dr. Richard Weindruch, Ricki J. Coleman, et al's, 20-year (so far) study of 30% calorie-restricted rhesus macaque monkeys at the University of Wisconsin's National Primate Research Center promises to up-end the studies on shorter-lived animal models that have preceded it. The incidence of tumors and cardiovascular disease in the experimental arm of the study is less than half that of the control group, and diabetes and impaired glucose regulation, while common in the ad libitum control arm of the study, has yet to be observed in the calorie-restricted experimental arm of the study. Note that the monkeys enrolled in the program ranged in age from 7 to 14 years, with an average life span of 27 years and a maximum lifespan of 40 years. This might translate into the human equivalent of beginning calorie restriction at an age ranging from 20 to 40, with an average lifespan of about 77, and a maximum lifespan of about 114. Note that these monkeys weren't allowed to drink, smoke, or cut up, and that they're living out their lives under controlled conditions. Fourteen of the unrestricted monkeys have died of age-related illnesses such as cancer and cardiovascular disease versus five of the calorie-restricted monkeys... approximately a 3:1 ratio. This points toward a 12%-to-13% increase in "youth span" for these monkeys that began calorie restriction at the human-equivalent age of something like 30. Dr. Weindruch estimates that this will lead to a lifespan extension of 10%-to-20%, and Harvard's Dr. David Sinclair suggests something like a 20% lifespan extension.
    I've been on a calorie restricted diet since August, 2003, although I've put on a little weight since I arrived at my minimum weight in spring, 2004. But given these primate results, it looks as though calorie restriction can pay off. And it certainly pays off in terms of easily measurable parameters. My blood lipid profiles and fasting glucose levels have been those of a teenager since they were first checked in early 2004.

(2) Rapamycin extends the lives of old mice
    At the same time that Drs. Weindruch and Coleman were reporting their good news, another research team revealed that the administration of the anti-rejection drug, rapamycin, had extended the maximum lifespan of old mice ( equivalent to 60-year-old humans) by 14% in female mice, even though the disease patterns were similar in both the experimental and the control arms. (This suggests to me that rapamycin's anti-aging mechanism differs from that of calories restriction (CR) in that CR delays degenerative diseases in mice and primates.) Calorie restriction is thought to up-regulate the action of the SIRT-1 gene, whereas rapamycin down-regulates the TOR (Target-Of-Rapamycin) gene and the associated signaling pathway. A parallel study that began with 270-day-old mice is showing similar results although it's too early for lifespan assessments.
    Rapamycin is an FDA-approved organ transplant anti-rejection drug. However, patients who take it are at high risk for pneumonia and fungal infections, so it's not recommended for general use. Still, there are other agents that can down-regulate the mTOR gene that might not have the untoward side effects of rapamycin. These will undoubtedly be further investigated. Also, for someone who's 100 and in a nursing home, risky experiments might be the lesser of two evils when weighed against the all-but-certain alternative of imminent death. And experiments might be performed on very old mammals, rather than putting them to sleep on the grounds that a slim chance is better than none.

(3) TA-65: The Regeneration of Telomeres
    Telomeres are the "shoelace tips" on the ends of chromosomes that keep them from unraveling. Most cells of the body start life with a fixed number of telomeres, and can't ever generate any more of them. Every time a cell divides, a telomere is lost, until eventually, the cell runs out of telomeres and can no longer reproduce correctly. (As the telomeres shorten, the risk of cancer rises.) However, certain cells such as bone marrow hematopoietic cells, skin fibroblasts, and epithelial cells express a telomere-lengthening activator called "telomerase" that allows them to extend their telomeres and to continue to reproduce. Normally, this telomerase is attached to the outer region of the nucleolus, but when meiosis begins, telomerase suddenly appears throughout the nucleus until cell division is complete. Then the telomerase is swept up and re-deposited in the outer regions of the nucleolus. Apparently, this sequestration of telomerase occurs in order to prevent the deposition of telomeres on both ends of broken chromosomes. However, in cancer cells, telomerase is present throughout the nucleus at all times. This renders the defective cancer cells immortal.
     The Chinese herb astragalus membranaceous contains a molecule dubbed TA-65 which triggers the production of telomerase. Now, a company called Sierra Sciences is offering TA-65 treatments (the Patton Protocol) to paying customers at a price of $2,860 for an initial evaluation (with insurance covering up to $860) plus $500 for a doctor's consultation, and $6,725 for every six months treatment, plus another $860 that may be covered by insurance. (The company recommends two years of treatment.)
    There is a dark side to this. Both William H. Andrews, Ph. D., the founder of Sierra Sciences and the former director of molecular biology at Geron Corporation, and Michael D. West, Ph. D., the founder of Geron Corporation and the CEO of Biotime. Inc., agree that providing whole-body telomerase has the potential to convert smoldering pre-cancerous lesions into immortal, full-blown cancers. Dr. Andrews argues that for the aged, the certainty of imminent death may offset the future risk of cancer. Also, short telomeres are strong risk factors for cancer. Dr. West points out that in mice, whole-body up-regulation of telomerase "clearly leads to an elevated risk of tumors". Dr. West, says, "Therefore, in my opinion, our best available mouse data argue that there is an unreasonable risk to treat a healthy individual with telomerase-activating compounds." He concludes, "It seems reasonable that for patients who are very old and/or are at high risk of death from age-related disease within five years, the Patton Protocol may be a reasonable tradeoff of risk and reward. Similarly, if telomerase activators could be given for shorter periods of time, or are administered to localized tissues that are a specific, near-term problem for the patient, such as the use of telomerase gene therapy to reset life span in a non-healing geriatric uskin ulcer, the trade-off might make sense."
    In the meantime, a number of early adopters... e. g., Ph.D's and M. D.'s... are testing Sierra Sciences' TA-65 Patton Protocol, some of whom have been in the program for more than two years. We'll see what happens.