Update
on Anti-Aging Developments
by
Bob Seitz
April
22, 2006
First,
the Good News:
The Pavement-Pounding Pace of Anti-Aging Progress
A
lot has happened in the last two months. Perhaps the “goodest” of the good
news is that anti-aging developments, including cheap, simple ways you can avail
yourself of them, seem to be happening fast. It reminds me of the period in 1944
just after the unveiling of the V-2, or the crescendoing announcements in
personal computers from 1974 onward Here are some specific developments over the
past two months.
(1)
Resveratrol Fed
to Killfish Extends Their Maximum Life Span 59%
Italian
researchers, in a paper in Current
Biology[1], have shown that killfish
fed resveratrol had a maximum life span 59% longer[2]
than a normally fed control group. Killfish are small fish with three-month life
spans.
This
is important because it’s the first experiment to show that orally
administered resveratrol will increase maximum life span in a vertebrate.
Following Dr. David Sinclair’s landmark 2003 discovery that resveratrol appears to be the number-one long-sought calorie restriction mimetic, it was quickly shown that resveratrol is almost immediately metabolized in humans, and it was argued that resveratrol would be ineffective as a calorie restriction mimetic. But apparently, ingestion is an effective way to administer resveratrol to animals.
Can
resveratrol’s calorie restriction effects be added to calorie restriction
itself, deepening the level of calorie restriction beyond what would be
practical by cutting calories alone? (Calorie effects are proportional to
the degree of calorie restriction that is being practiced.)
In
any case, resveratrol could be a worthy addition to life extension
strategies.
One
note of caution: The authors of the resveratrol paper point out
that there was an initial increase in morbidity in their fish. They suggest that
resveratrol might be somewhat toxic. Presumably, red wine extract should
be safe in moderate doses. Still, caveat emptor….
One question is: how do you translate doses of resveratrol killfish to equivalent human doses? One day in the life of a killfish would equate to about a year for us. Do we divide the maximum-longevity killfish dose of 150 mg./kg. of body weight by 365? That would give us about 0.4 mg./kg for the human-equivalent daily resveratrol dose, or about 24 mg. (approximately what’s in Longevinex’ resveratrol) per day for someone who weighs 60 kg. (132 pounds).
If
resveratrol and calorie restriction increase life spans additively, then
the long awaited, over-the-waterfall chain reaction in the conquest of aging
might possibly be at hand. Surely sometime soon, the public is going to awaken
to the existence of something (CR and its mimetics) that can virtually eliminate
the chances of artery diseases, substantially delay the onset of degenerative
diseases, including arthritis, preserve youthful appearances, and extend life
spans by a decade or two. And that, I think, is going to trigger a runaway
effort to conquer aging.
(2) Calorie
Restriction Improves Diastolic Function in Humans
The Washington University researchers who reported in a National Academy of Sciences paper[3] in April, 2004, that a complement of 18 calorie restricted subjects were exhibiting dramatically improved cardiovascular risk profiles has followed up that original paper with a follow-on study[4] in the Jan. 17, 2006 Journal of the American College of Cardiology. This paper shows that the diastolic functions of the hearts in 25 calorie-restricted individuals was, on average, about 17 years younger than that of fully fed matched controls.
The cardiovascular risk factors examined in the first (2004) Washington University study are secondary biomarkers of aging. They are parameters that tend to increase with age, but they are amenable to medications and lifestyle changes that will, for example, lower the levels of total cholesterol and raise the levels of HDL. Diastolic function, on the other hand, is a primary biomarker of aging, and is a measure of the elasticity of the heart. It’s (to the best of my knowledge) unaffected by exercise, and steadily declines over the course of a lifetime. Improving diastolic function might be construed to be a partial reversal of aging, at least insofar as diastolic function is concerned. One interesting point that was elucidated at the conference: CR decreases the stiffness of blood vessels by shrinking cartilage that develops around blood vessels with age rather than by breaking up cross-linkages. Promising natural cross-link breakers are carnosine, benfotiamine, and pyridoxamine (one of the three vitamers that comprise vitamin B6).
A recently completed Washington University study, Calorie Restriction Appears Better Than Exercise At Slowing Primary Aging, reveals results that are, perhaps, more fundamental and important then the cardiovascular measurements of calorie restricted humans that Washington University researchers have unearthed. This latest study showed that the calorie-restricted have lower levels of tumor necrosis factor (a biomarker of inflammation), and T3 (triiodothrronine) (though not of thyroxin-T4- and thyroid stimulating hormone-TSH). Lower levels of T3 mean lower body temperatures, lower cellular body weights, and to some extent, free radicals. The CRANies also have much lower levels of insulin (by a factor of 3 or 4) and much lower levels of Insulin Growth Factor 1, all of which are found in calorie restricted animals, and all of which suggest a reduction in the rate of primary aging. This latest Washington University study also examined endurance athletes with the same body fat percentages as those on calorie restriction. The endurance athletes ingested 2,700 calories a day versus 1,800 calories a day for the calorie restricted group. In spite of the fact that the endurance athletes had the same body fat levels as the CRANies, their average level of T3, while lower than the average for the control group, was closer to the average T3 level of the control group than to that of the calorie restricted group. The same situation occurred with respect to triglycerides and HDL. C-reactive protein, fasting glucose, and blood pressure levels are also much lower only in the calorie restricted.
Another
anti-aging supplement that might make a difference is the slow release form of
the R+ enantiomer of alpha-lipoic acid[5].
(3)
Other Follow-On Studies of Calorie Restriction in Humans
Capitalizing
upon the success of the original Washington University pilot study, the National
Institute on Aging has funded four parallel succeedanea with Washington, Tufts,
and Duke universities, and with the Pennington Biomedical Research Center in
Baton Rouge, Louisiana, in a program called CALERIE. These two-year studies will
be completed within the next couple of years.
(4) Protandim,
GliSODin, and SODzyme
Last
year, Tommie Jean called me to watch an ABC TV program extolling a new
breakthrough in aging. It was about something called Protandim[6].
Protandim is the trade name for a capsule that boosts the endogenous
production of Superoxide Dismutas (SOD), Catalase. and Glutathione
Perioxidase. Superoxide dismutase, catalase, and glutathione perioxidase
are the body’s own primary antioxidants. Previous attempts to deliver these
endogenous antioxidants in supplement form failed because they’re unable to
survive the GI tract. Unfortunately, their levels decline with age, rendering us
ever more vulnerable to free radical damage. For decades, people have taken
vitamin E and vitamin C for antioxidant protection, with negligible results.
Apparently, boosting vitamin C and vitamin E levels doesn’t affect
health unless an organism is deficient in them.
In
1954, Denham Harman, at the University of California, Berkeley, propounded the
free radical theory of aging. Could
aging be caused entirely by free radical
damage
accumulating over a lifetime? Researchers began to feed antioxidants to
laboratory animals hoping to slow their rates of aging.
Alack and alas! Although feeding antioxidants to lab animals extended
their average life spans (by 30% in the graph shown above), they didn’t seem
to affect the underlying rates of aging or extend maximum life spans.
The
take-home message was that something else—maybe genes—are controlling the
aging process.
Recently,
Joe McCord, the co-discoverer of superoxide dismutase, identified five
botanicals that elevate the levels of these intracellular antioxidants to values
appropriate to young adults, eliminating these antioxidants’ age-related
declines[7].
The five botanicals are turmeric, 75 mg., green tea extract,
75 mg., silymarin (milk thistle seed), 225 mg.; bacopa, 150 mg.;
and ashwagandha, 150 mg. Their SOD/catalase-stimulating effects
are thought to be additive rather than synergistic. Dr. McCord chose using small
additive doses of five SOD-enhancers rather than one large dose of any
one of them because (I suspect) he was conducting the moral equivalent of Phase
I and Phase II trials, and didn’t want to risk possible side effects brought
on by a large dose of any one of the ingredients. The point is; you can probably
sprinkle turmeric on your food and drink green tea and get the
same effect. However, I should also mention that there’s a minimum and maximum
effective dose for this, and 675 mg. of Protandim is probably somewhere
close to an optimum dose. (You have to be careful. Too much of this can promote
oxidation rather than reduce it.)
Turmeric
is also a potent anti-inflammatory like aspirin.
In
a small pilot study involving about 20 subjects, Dr. McCord found that Protandim
reduced the levels of oxidative stress in his subjects to youthful levels.
The
Life Extension Foundation says, “SOD, for example, may be up to 3,500 times more potent than
vitamin C in quenching the dangerous superoxide radical.[8]”
The reason is that vitamins C and E quench free radicals stoichiometrically by
sacrificing a molecule of vitamin for every free radical quenched. The cell's
antioxidants operate catalytically, neutralizing free radicals without being
consumed in the process.
Quantitative differences of this magnitude can become qualitative, and this is what Dr. McCord is hoping. There are some animal experiments involving transgenic animals modified to overexpress SOD or catalase, and in both cases, show significant maximum life span extensions. However, the touchstone will probably be life span studies feeding Protandim to mice. We might want to go slow with this until that takes place.
There
are societies in which turmeric is widely consumed, and societies in which green
tea is widely consumed and some societies in which both are ingested each day,
and yet, the members of these societies don't, to the best of my knowledge, live
dramatically longer than members of other societies. There may even be
individuals in India who consume turmeric, green tea, and one or more of the
other three herbs: milk thistle seed, bacopa, and ashwaganha.
Meanwhile,
back at the North Pole,
Safety
Issues
Although
turmeric and green tea have been around for thousands of years,
that doesn’t necessarily make them safe. Who would have thought 60 or 70 years
ago that coffee cream, butter, and eggs could be harmful to your health? I’m
not aware of much in the way of safety studies of the long-term effects of turmeric
(cumin) and green tea. And
if that’s true of such venerable tisanes as teas, think about resveratrol!
David Sinclair is said to have muttered, in 2003, veiled cancer warnings about resveratrol.
It was hard to know how to assess his alleged remarks because at that time, Dr.
Sinclair was raising $45 million in venture capital to found Sirtris Corporation
in order to try to develop and patent synthetic resveratrol analogs so
that in a decade or so, they could be used as prescription drugs to combat
diabetes, heart disease, and/or other debilitating diseases. However, Dr.
Sinclair and his co-workers have launched life span studies of resveratrol
in mice that should mature within a year or two.
Accordingly, after reading what I’m writing, I’ve decided to quit
taking resveratrol (red wine extract) until a bit more safety
information is available regarding its consumption. As red wine extract, it
should be relatively safe, but we (or at least I) don’t know the proper dosage
levels in humans.
U-Shaped
Curves
The
effectiveness of many pharmacological agents is described by a U-shaped curve.
Too little is ineffective. Too much can sometimes worsen the condition that the
pharmacological agent is trying to alleviate. There’s a happy medium.
Metformin
As
I’ve mentioned before, in gene chip studies performed in 2001 by Dr. Steve
Spindler at the University of California, Riverside, metformin, alone
among diabetic drugs, generated most of the same gene chip changes as CR. A
1980’s life span study in mice used a metformin precursor called phenformin
to extend the maximum life span of the mice by 23%. A quick, recent life span
study of metformin in mice at the National Institute on Aging indicated a
maximum life span extension of about 20%, and an ongoing life span study of the
life span effects of metformin on mice sponsored by the Life Extension
Foundation is slated to report its results by September, 2007.
Why
Anti-Aging Pills Might Not Be Altogether Practical
If
metformin is a CR mimetic, I began to wonder why it isn’t used
off-label for such purposes as elevating HDL.
Then it hit me. Medicine is (necessarily) very conservative. Metformin’s
predecessor, phenformin, caused 60 deaths in a million patients from
lactic acidosis, and was withdrawn from the market. Its proponents said that a
handful of prescribing physicians failed to warn their patients about feelings
of extreme fatigue and muscle weakness, but phenformin was taken off the
market just the same. Its successor, metformin, is safer (or maybe
prescribing physicians are simply more aware of its possible lethal side
effects), but patients and doctors are still advised to be on the lookout for
adverse conditions. What this means is that safe dosage levels are going to be
held down low enough that drugs allegedly kill, at most, a few patients per
million. I say “allegedly” because (1) the death of someone who’s already
very sick might be falsely attributed to metformin if it could justify a
multimillion-dollar lawsuit, and (2) we’re all different, and different people
will respond to metformin with different sensitivities. If we’re
experimenting with mice, we don’t care if it kills 2% of our experimental arm,
but if we’re experimenting with humans, we won’t accept a 0.001% lethality
rate. And what’s true for metformin may be true for all CR mimetics and
anti-aging pills.
For
human safety reasons, the medical community may need to keep recommended dosage
levels of anti-aging drugs too low to realize most of their potential benefits!
(5)
My Bloodwork
I’ve
previously mentioned the dramatic rise in my HDL in February, 2004, after I had
been practicing calorie restriction (as in “losing weight”) for six months.
Since then, my family doctor hasn’t seen it necessary to retest these
parameters. Consequently, earlier this month, I purchased a blood chemistry/CBC
test through the Life Extension Foundation.
I wanted to see if my dramatic rise in HDL had been maintained. (Statins
will lower levels of LDL but they won’t usually raise levels of HDL Drugs that
will elevate HDL are current targets of developmental opportunity among
pharmaceutical companies.)
When
my results came back, my HDL this time was 84, up 65% from my pre-CR days, and
the ratio of total cholesterol to HDL was slightly less than 2.4, down 40% from
my pre-CR days. (In the Framingham Heart Study, it’s alleged that no one with
a TC/HDL ratio of 2.5 or below ever had a heart attack.)
Apparently,
calorie restriction is still working.
Calorie
restriction also lowers other inflammatory cardiac and cancer risk factors such
as homocysteine and C-Reactive protein.
And Now, the
(Possibly) Bad News):
From April 5 through 9, I attended the Fourth Calorie Restriction Conference in Tucson, Arizona. One shocking message from the speakers was that CR may not slow aging in humans, and if it does extend maximum life spans, it’s by no more than two or three years. Several of the speakers seemed to be inclined toward this outlook. Cambridge University's Aubrey de Gray, in a presentation entitled, "The Unfortunate Influence of the Weather Upon Human Lifespans", presented his hypothesis that CR should yield minimal life extensions in humans. Dr. de Gray began by observing that the early deaths of animals from predation precludes late reproduction. Animal species must reproduce early. But early reproduction requires rapid growth, and rapid growth goes with rapid aging and cancer. (Whoa! What about predators at the top of the food chain, like the big cats and grizzly bears? What about whales? Also, red sea urchins and rough-eyed rockfish reach sexual maturity early but live and continue to reproduce for at least 200 years. ?) Next, Dr. de Gray noted that starvation of worms multiplies their effective lifespans by a factor of three. Fruit flies go into diapause with the onset of winter to achieve a similar three-to-one ration in lifespans. Grasshoppers go into diapause during an arid summer. "So why are lifespans in mice increased only 40%?" Dr. de Gray observed that calorie restriction is designed to help animals survive a drought or a famine, and very few droughts or famines last 10, 15, or 20 years. A year or two is the longest most droughts or famines are apt to last. evolution will tend to provide no greater capabilities than the long-term environment requires ("use it or lose it"). If an organism only needs to survive for an extra two or three years, then over time, excess capacity will be bred out of the organism. So two or three years is probably the greatest life extension that humans can expect to experience with CR.
Dr.
de Gray then pointed out that CR has lengthened the average lifespan of
Okinawans by less than two years over the average lifespan of the Japanese.
(Michael Rae observed from the audience that the Okinawans were on 20% CR only
until the 1960's and that they suffered from severe dietary deficiencies and had
no modern medical care. Since the 1960's, they've become overweight junk food
addicts.) Dogs on 25% CR experienced a maximum lifesapn extension of only about
10%. It's clear that calorie restriction improves the health of monkeys and
humans, but major lifespan extensions...? It appears that CR increases lifespan
by something like the same amount rather than by a percentage.
Others Who
Have Reached Similar Conclusions: Eric Le Bourg:
Eric
Le Bourg at the Centre de Recherche sur la Cognition Animale observes
that species that are able to migrate (including humans) would not be expected
to respond to calorie restriction because it would be easier for them to migrate
to better feeding grounds than to hunker down and adapt through caloric
restriction. Dr. Le Bourg begins with the assertion that CR doesn't extend the
lifespan of the common housefly or the Mediterranean fruitfly. He and a
colleague have called into question the reported CR-induced, lifesapan
extensions of drosophila melanogaster. He cites Ed Masoro and Steve Austad who
postulated in 1996, that species not facing unpredictable short-term food
shortages could have lost their ability to respond to DR*. For instance,
vegetation-consuming monkeys living in tropical forests should not show a
longevity increase when subjected to DR. since their environments are quite
stable all year and year after year." (I would add to this
pelagic species such as tuna that live in the stable environment of the world's
oceans, and that would have the ability to migrate long distances if local
problems arose, although it's hard to imagine much variation in oceanic
environments.) He then notes that "no positive effects on longevity in
Rhesus monkeys has been observed by Ingram, et al. (2005): at least 12 years
after the onset of DR experiments (17 years for some animals, n > 80), 50% of
the control monkeys had died, the very same percentage being observed in monkeys
subjected to DR*. Such a result is clearly not in favor of a positive effect of
DR on human longevity, provided that monkeys and humans would respond similarly
to DR."
*
- DR = "Dietary Restriction"
Others
Who Have Reached Similar Conclusions: Lloyd Demetrius:
Lloyd
Demetrius, a Harvard associate, has reached the same conclusion (that CR will
have little effect in humans) following a different line of reasoning. He
argues that the response to CR is based upon an organism's metabolic stability. "Mice
are not small people", Dr. Demetrius argues. Mice are an opportunistic
species whereas humans are an equilibrium species. "In an opportunistic
species, evolution will result in early sexual maturity, large litter size, and
metabolic flexibility due to the high vulnerability to random changes in
metabolic networks. In an equilibrium species, evolution will result in late
sexual maturity, small litter size, and metabolic robustness due to the relative
insensitivity of the system to random changes. The effect of CR on the two
species will then be different. If we make the hypothesis that CR increases the
stability or robustness of the metabolic network by increasing the metabolic
efficiency and enhancement of homeostatic regulation in cells, we can predict
that CR will induce large changes in an opportunistic species by increasing its
robustness, whereas it will have weaker effects on an equilibrium species, in
which robustness is already achieved. From this, Dr. Demetrius predicted that
the response to CR with an increase in lifespan will be marginal in humans owing
to the robustness or stability of their metabolic networks and the evolutionary
history of the species."
Some Projected Consequences of These
Theses:
Other Factors That Might Affect Life
Spans Besides Droughts and Famines:
The Effects of Inhabiting the Tropics Versus the Temperate Zones
The
turns of the seasons would seem to force most temperate animals to grow fast within a year. In the temperate zones, oestrus and birthing
occurs in the spring so that new animals will be sufficiently mature to weather
the harsh winters. Animals must store up fat during the summers to help them
survive food shortages during the winters when nothing edible blooms and snow
may cover the ground. This is in contrast to the tropics, where, food is
available all year around.
Bottom Line: Temperate-zone animals must grow up in less than a year
whereas tropical animals don't face an annual reckoning.
The Effects of Territoriality Upon Animal Migration:
Many animal species, including humans, might have been biologically capable of migrating away from environmental hardships, but this would have required moving into the territories of other animals, triggering conflict. If times grew harsh in Quebec, Algonquins who migrated into New York State might have triggered war with the Mohawks, the "keepers of the Eastern Door" for the Iroquois. If times were bad enough for the Algonquins to try to move south from Quebec, they probably weren't flush for the Mohawks.
Similar
behaviors might have been evinced by other predators attempting to move into
another predator's territory.
The Malthusian Predation Cycle:
Birds:
Birds in general, and large passerine birds such as wild geese, in particular, reproduce each spring, giving birth to 3 to 6 chicks each spring that must reach maturity by fall in order to migrate south with the flock. Canada geese live up to 24 years in the wild. Does that make geese an opportunistic species? Their wild populations can increase by 10% to 17% a year, a fact that's currently threatening an unwanted population explosion. (This is in contrast to human populations that might typically increase as much as 3% a year.) (It's worth noting that anthropologists It would seem to me that Dr. Demetrius' argument would put wild Canada geese closer to mice than to humans. On the other hand, since they can migrate long distances to escape deleterious conditions, Dr. Le Bourg probably wouldn't expect them to evolve CR.
One
of the experiments cited in support of this thesis was the “Vallejo” study
conducted in Spain from 1955 to 1958.
The Vallejo Study
Sixty
healthy individuals aged 65 and up (with an average age of 72) living in a religious
home for the elderly, were put on alternate-day calorie restriction, ingesting
2,300 calories on one day, and 900-calories (of fruit and milk) on the next.
This CR contingent was compared with a matched control group of 60 normally fed
residents who received the full 2,300 calories every day. At the end of three
years, 6 (10%) of the calorie-restricted subjects had died, compared with 13
(22%) of the control group, but this wasn’t statistically significant because
the numbers were so small (6 and 13). In other words, the mortality rate in the
CR group was about half that of the control group. The calorie-restricted group
had registered a little over half the trips to the hospital experienced by the
control group. This was statistically significant, because the numbers of
occurrences were much larger.
I
inferred that the carry-away message from this experiment was supposed to be
that the subjects on the calorie-restricted diet didn’t live 10 or 15 years
longer than the controls. But the study only lasted for three years. What would
have happened if they had continued the study until the patients in both groups
had all died? CR obviously helped the people who were on CR, but they would also
have had pre-existing conditions such as atherosclerosis or occult cancer. CR
might have raised their HDL levels and lowered their cholesterol levels, but it
would have required several years for the full effects of CR to kick in.
Also, we know today that the transition to a CR diet must take place
slowly in the elderly. Then, too, their nutrition wasn't what we might prescribe
for them today..
CR
roughly halved the mortality rate and cut the hospital visits in half.
What
would have happened if you had started with 50-year-old health enthusiasts?
The
Most Senior CRANie of Them All
Ralph
Cornell, of Massillon, Ohio, began calorie restriction in 1953 when he was 50
years old. He’s now 103. Until two years ago, when he was 101, he drove to and
from his real estate office every day. (I believe he ran a mile in 2004.) Then
he fell and broke his hip (osteoporosis?), and now needs a walker to get around.
He’s also had a heart attack.
He’s
part of Paul McGlothin and his wife’s extended family, so Paul knows Ralph
quite well. Paul says there may be some extenuating circumstances surrounding
Ralph’s failing health. After all, he was the first, and issues of nutrition
and medical care would have broken new ground.
Ralph’s relatives lived into their nineties, so he has good genes. The odds of reaching 103 from 95 through the luck of the draw are about one in ten.
I
have to admit that clean living and exercise could have given Ralph his
centenarian status without invoking CR.
The Purina Study
of Labrador Retrievers
In
1987, the Purina company initiated a small study of 48 Labrador Retrievers, 24
of which were put on 25% calorie-restricted diets starting at 8 weeks. The study
lasted 15 years until the last dog was hanged—uh, buried. The control group
was slightly restricted from the age of 3.25 onward to prevent overweight.
The last dog in the control group died at 13.3 years, while the last dog
in the CR group lived until it was “nearly 15”… about a year-and-a-half
longer, or about 11% longer than the slightly restricted control dog. The median
age at death for the CR group was 22 months (15%) greater than the median age
for the control group. When only one member of the control group was left, 18
members of the CR group were still running around. When the last member of the
control group had died, 6 of the CR Labradors were still living. And the health
of CR group was much better than that of the control group at every age.
The
maximum life span, defined as the average age at which the longest-lived 10%
died, was a little longer in the CR group but the difference wasn’t
statistically significant at the p<0.05 confidence level (although the oldest
retriever in the CR arm outlived the oldest dog in the control group by about 18
months). Of course, the longest-lived 10% in each group consisted of 2.4 dogs,
which doesn’t lend itself to very accurate statistics.
The key issue was that although the CR group outlived the control group, they did so by 10%-to-15%, and not by the 25% that you’d have expected in mice, or about 50% to 60% of the life span extension that you’d expect in mice. These Labrador retrievers lived about 5 times longer than mice, and about 1/6th as long as humans.
It's
worth noting that
Otherwise,
I consider this study to be an endorsement for CR.
The Okinawans
The
Okinawans practice 20% calorie restriction (38% as children), eat at
least 7 servings of vegetables and 5 servings of fruit a day, eat fish several
times a week (along with very little meat), exercise, and live laid back and
sociable lives. They also drink turmeric tea (and presumably, green tea). Not
only do they live a long time, they’re also very healthy and active into their
nineties.
It
might be worth noting that their 20% calorie
reduction is measured with respect to the calorie intake of the average Japanese
But given the Okinawans' childhood food restraint, they might be shorter and
smaller than the Japanese, in which case, their normal adult calorie requirement
might be a bit less than that of the typical Japanese. At 20% fewer calories
than the Japanese, how calorie-restricted are they? To
know the answer to that question, we would have to know their their percentages of body fat. (That information may already be available as
a part of the Okinawa Centenarian Study.)
In
1960, the life expectancy for the average Okinawan was 72 when Japan’s life
expectancy was 67.5, Sweden’s life expectancy was 73 and the U. S. stood at
not-quite 70. By 1998, Okinawa had
reached 81.2, Sweden was at 79, the U. S. was about 76, and Japan was about 80.
The Okinawans had surpassed the Swedes to become the longest-lived people in the
world. But this is a case of “damned with faint praise”.
Given their presumed-to-be-extremely-healthy lifestyles (never mind
calorie restriction), why aren’t they living longer than 81.2 years?
Long-term-vegetarian California Seventh-Day Adventists had an average life
expectancy of 84.5 years[9],
and, perhaps, higher if they ate nuts and exercised. In fact, "the life
expectancies of California Adventist men
and women are higher than those of any other well-described natural population"
(from speeches at Oxford Vegetarians). Furthermore,
the life expectancies of the Okinawans rose very rapidly since 1960, and this
among a people who, supposedly, already practiced some of the best health habits
in the world. So what’s going on?
And the next question is: what does this life expectancy mean? Is it a projection of future life expectancies, measured from 1998 onward (to the year 2079.2)? If so, how did the actuaries factor in the overweight condition of younger Okinawans? On the other hand, if it's the average lifespan of people who lived until 1998, it would be incorrect to compare it with the future projections of lifespans in other countries.
I’m
suspicious about comparisons like this between the third-word agrarian societies
and first-world post-industrial societies. The Okinawans may be doing a lot
better than casually meets the eye, a third-world player beating the first-world
players at their own game. Life expectancies jumped sharply in first-world
countries because of clean water supplies, childhood vaccination programs,
public health programs, and personal hygiene during the first half of the
twentieth century. What was happening in Okinawa during those years? What about
bacterially contaminated water? What about parasites such as body lice, and
infectious loads?
How much should
20% calorie restriction affect their life spans? First, we
would have to know what their life spans would be without calorie restriction.
Okinawa’s culture is separate from the rest of Japan so it’s not easy to
say. The U. S. arrived during World
War II and stayed until 1978, so penicillin would have been introduced to
Okinawa around 1945, but not necessarily to the indigenous population. If
calorie restriction worked as it does in mice, it would have extended their life
spans by 20%, from 67.7 to 81.2. If it worked the way it does in Labrador
retrievers, it would have extended their life spans by 10%, from 73.8 to 81.2.
Both 67.7 sad 73.8 would be respectable life expectancies for rural third-world
countries.
It’s worth noting that, Kamato Hongo, the world’s oldest person for several years, hailed from an island near Okinawa. Ms. Hongo drank green tea and herbal (turmeric?) tea. The oldest Okinawan so far lived to 113 out of a population of about 1.25 million inhabitants. Another one was 108 and was going fishing every day. Many of the world’s oldest super-centenarians hail from this area.
The bottom line: I
don’t know enough of the gritty details of the Okinawa story to assess it.
But
the fact remains that the Okinawans haven't lived 20% longer than the Japanese.
Life
Expectancies
One of the first questions to be answered is: what's the maximum life expectancy for humans? It certainly isn't 122. That's the life expectancy of, perhaps, one in hundreds of millions. Also, it isn't the life expectancy of someone born today. That's a projection into the future. If we apply the same yarf stick that we use for animals, the maximum lifespan for all races in the U. S. would be the average lifespan of the longest-lived 10% of the U. S. population that is reaching that lifespan today, and that number appears to be about 88. (The average lifespan today would be about 70.) This means that a 40% extension of the human lifespan, presumably achievable only by restricting calorie intake 40% or more from the time of weaning, would lead to a maximum (1-in-20) lifespan of about 125 years, and an average lifespan of about 98 years of age. A more reasonable lifespan extension for someone who began 30% CR at the age of 30 (in 1950), might be 15%-to-20%, which would amount to a lifespan extension of 13 to 17 years, leading to a maximum, 1-in-20 age at death of 101 to 105--well within the envelope of current human lifespans. (A 15% to 20% extension of the average human lifespan would be about 10 to 14 years, leading to an average lifespan, if a large population of today's senior citizens had begun practicing 30% CR from age 30 back in the early fifties, of 80 to 84.) For someone starting CR at the age of 50, like Ralph Cornell, the lifespan extension might be expected to be, perhaps, 12 to 15 years.
These numbers are based upon the general population. What about a population that focuses on good health?
Seventh-Day Adventists who practice what they preach might be a representative population. Their includes good nutrition, moderate exercise, and eating nuts 5 or more times a week (which, for some reason, adds another year-and-a-half to the lifespan). For those surviving to age 30, their health habits add an extra 7.3 years to men and 4.4 years to women. For vegetarians, the gain is 9.5 and 6.1 years, respectively. For someone who is in their mid-30's today, the average life expectancy is about 74. Without CR, the average life expectancy for someone who is 35-37 years old who practices very good health habits, including eating nuts five or more times a week, might be 80, with a maximum (1-in-20) lifespan of, perhaps, 94. (I'm adding 10 years to the average lifespan but only 6 years to the maximum lifespan because of range compression at upper age levels.) Adding an assumed 13 to 17 years to that assuming that this individual starts CR today might give a projected average lifespan of 93 to 97, and a maximum (1-in-20) lifespan of about 107 to 111.
A lifespan of 150 years would represent a 70% increase over today's maximum lifespan of 88, and a 23% increase in life span over the one-in-several-hundred-million lifespan of Jean Calment. For several hundred million people starting CR at 35=37, the one-in-several-hundred-million lifespan corresponding to Jean Calment might be 135 to 140... a bit less than the 150-year lifespan projected for CR because of the impracticality of starting CR in humans at weaning.
An
examination of the Center for Disease Control’s Survivorship tables[10]
reveals some very interesting information. Out of 100,000 people born in my
parents’ birth years, 1900-1902, only 31 of the 100,000 actually became
centenarians. By the time I was
born 30 years later, the projected number of centenarians in 2030-2032
had doubled to 62. Today, 70 years after that, the projected frequency of
centenarians for babies born in 2100-2102 is 2,100… almost 70 times the number
in my parents’ generation!
The average life expectancy is shown as rising from 47 in 1900 to 77 in 2000—an increase of 30 years. (A part of this disparity in lifespans is a consequence of infant mortality. Among people born in 1900-1902, about 20% died before age 20, compared with 2% for infants born today.)
The rise in life expectancy for the longest-lived 10% of the population goes from about 86 in 1900-1902 to a projected 99 for children born in 2000-2002… an increase of about 13 years. And the life expectancy for a centenarian in 2000-2002 is 1.58 years, compared with a projected life span for centenarians of 2.7 years in 2100-2102… a paltry 1.12-year increase. It would be tempting to conclude that there is an elastic limit a little above 100 to the natural human life span if it weren’t for outliers like 116-year-old Kamato Hongo.
Dr. Jay Olshansky has argued that these
trends, with average life spans rising by ¼-year per year will slow down in the
21st century, and life expectancies might actually fall because of
obesity, antibiotic-resistant diseases, etc.
Call By a Well-Known Life Extension
Skeptic for a $3,000,000,000 Federal Program to Slow the Rate of Aging by Seven
Years
Dr.
Olshansky has recently called for a $3,000,000,000 program to try to slow human
aging by 7 years (8%? 9%?).[11]
Monkey Business
In
1987, Drs. George Roth, Donald Ingram and Mark Lane at the National Institute on
Aging began a study of long-term calorie restriction with 30 monkeys. This has
since expanded to nearly 200 monkeys with three basic age cohorts: very young,
young-adult, and old (equivalent to the age of 60 in humans). From the
program’s inception, the CR group has exhibited the characteristics common to
other species on CR: lowered fasting insulin levels, lowered fasting blood sugar
levels, lowered body temperatures, and elevated HDL, and insulin sensitivity, to
name a few. Dehydroepiandrosterone (DHEA) and alkaline phosphatase levels in the
CR monkeys, thought to be meaningful barometers of aging, aren’t declining
with age the way they are in the full-calorie group. The CR monkeys are smaller,
younger-looking, and healthier than the ad libitum-fed monkeys. The CR
monkeys have about 7% body fat, in comparison with 15%-20% body fat among the
controls.
Some
accidental deaths have occurred over the years, such as overcooked food causing
deadly gastric bloat. This might muddy the waters when the time comes to crunch
the final numbers.
These
monkeys are now 19 years into the study, with average life spans of about 27
years, and “maximum” life spans (defined as the average age at death of the
longest-lived decile) of... 35(?) years (corresponding to human ages of 75 and
97-). It will be 2014 before they reach the 27-year mark.
At
the Fourth Calorie Restriction Conference, it was revealed that the control
group of monkeys in the NIA study are becoming so depressed in their middle age,
cooped up in their cages, that they’re eating no more than the CR monkeys.
They have to be cajoled, and fed candy to get them to eat.
In the meantime, at the University of Wisconsin, about 30% of the fully fed monkeys have died, versus 10% of the calorie-restricted monkeys. The CR monkeys have had two cases of cancer versus five in the controls (out of 76 monkeys). The controls have had twice the death rate from aging -related diseases like heart failure and diabetes.
The
oldest member of the CR group, C58, set a new longevity record by dying last
year at the age of 41. The second-oldest confirmed monkey life span was 36, with
an unconfirmed report of another monkey who reached 39. These latter two monkeys
were fully fed, but they’re also the oldest monkeys on record (1 in 1,000? 1
in 10,000?) Note that C58 presumably wouldn’t have been calorie restricted
until its last 18 years, when the NIA Aging in Non-Human Primates program began.
That means it would have been about 23, equivalent to 69 in human terms, when
its calorie restriction began.
These non-human primates seem to me to be a litmus test regarding whether or not CR will slow aging in humans.
National Institute on Aging researchers Don Ingram, George Roth, Matt Lane, M. A. Ottinger, S. Zou, R. de Cabo, and J. A. Mattison have just pre-published a Biogerontology paper
"Based
on results emerging from long-term studies of dietary restriction in rhesus
monkeys, we offer our views regarding whether dietary restriction can increase
longevity in humans. Because lifespan data in monkeys remain inconclusive
currently, we respond that 'we do not for sure.' Based on the vast literature
regarding the effects of healthy, low calorie diets on health and longevity in a
wide range of species, including humans, and based on data emerging from monkey
studies
suggesting that dietary restriction improves markers of disease risk and health,
we respond that 'we think so.'"
In rhesus monkeys, calorie restriction has had pronounced effects. A University of Wisconsin team led by Richard Weindruch has been studying 76 monkeys for more than a decade, half on low-calorie diets and half in a control group that eats normally.
The low-calorie animals weigh about 30 percent less and have 70 percent less
body fat than the controls, as well as lower insulin levels. The
calorie-restricted monkeys have had two cases of cancer, compared with five in
the controls. The controls have had twice the death rate from aging-related
diseases like heart failure and diabetes. About 90 percent of the monkeys on
low-calorie diets are still alive, compared with only about 70 percent of the
controls.
"Evidence
emerging from studies in rhesus monkeys suggests that their response to CR
parallels that observed in rodents."
Animal research suggests a number
Of
course, even if CR doesn’t slow the rate of aging in humans, its health
benefits, and its ability to extend your life span would seem to me to be
more than worth the price of admission.
Summing
It Up
Whether
or not CR slows aging in humans, if it gives us, as individuals, another ten or
fifteen years of healthy living, that will be good enough for now (2006). And
the effects of CR in humans are dramatic. The Washington University researchers
continue to find evidence that calorie restriction in humans produces the same
kinds of fundamental changes in humans that they do in smaller mammals. In
my opinion, the idea that CR will have little or no effect in humans won’t
hold water, nor will the idea that CR started later in life will afford minimal
or no benefits. My own experience and that of others such as Ralph Cornell
suggests otherwise.
For
the purpose of allocating research priorities, I think it’s important that we
know whether CR slows aging, or whether it merely improves health and enables
us, as Bob Cavanaugh puts it, to reach our full genetic potential.
If
CR extends average life span without slowing the rate of aging and extending
maximum life span, then we have to postulate two different kinds of calorie
restriction effects: one kind that increases average life span and another kind
that extends maximum life span. I could certainly be wrong, and I may change my
tune without warning as I learn more, but right now, I don’t think that’s
the case. I suspect that CR will shift the survival curve to the right, just as
it does in all other species that have been tested to date, rather than changing
the shape of the curve. I also speculate that it will slow aging in humans and
extend maximum life span by something like the same percentage that it increases
maximum life span. It may be that maximum human life spans are extended by only
10% or 15% for 30% calorie restriction, rather than the 30% maximum life
extensions that are observed in rats and mice, but I think there will be some
sizable effect and I think that much of this effect will occur for those who
start CR later in life. I’m heartened by the story of C58, above. C58 has
already set a new record for rhesus monkey longevity and the program is just
getting started.
Also, it’s hard to imagine the resounding improvements in
so many age-related parameters having no influence upon maximum human life span
as well as average life span.
Based
upon my review of the literature for this article, I'm still hopeful that CR may
add another 15 to 25 years to our lives, 10 or 15 of which would be the result
of the slowing of aging.
__________________________________________________________________________________________
[1]
- http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VRT-4J6NSR8-12&_coverDate=
[2]
- http://www.sciencedaily.com/releases/2006/02/060206232855.htm
[3]
- http://www.pnas.org/cgi/content/abstract/0308291101v1
[4]
- http://www.sciencedaily.com/releases/2006/01/060113112537.htm
[5]
- http://www.relentlessimprovement.com/learn/rlipoic_faq.php
[6]
- http://www.protandim.com/
[7]
- http://www.protandim.com/pdf/Protandim%20FRBM%202006.pdf
[8]
- http://search.lef.org/cgi-src-bin/MsmGo.exe?grab_id=0&page_id=1360&query=SOD&hiword=SOD%20
[9]
- http://www.davidephraim.com/NEWS/health_news.htm
[10]
- http://www.cdc.gov/nchs/data/nvsr/nvsr53/nvsr53_06.pdf
[11]
- http://www.fightaging.org/archives/000781.php