Must
We Grow Old? - Redux
June 16, 2004
Are We Living in the Last Days of Old Age?
As this article describes, some startling discoveries have
recently been made--in particular, the discovery that caloric-restriction
partially reverses aging! I now think that we may be witnessing the last
generation that must grow old.
Do You Know That in a Few
Months of Dieting, You Can Partially Subtract a Decade or More from Your Biological Age,
and Thereafter, Somewhat Slow Your Rate of Aging?
It's been known for decades that caloric
restriction will slow the rate of aging in animals and plants, but what wasn't
known until recently is that dietary restriction begun later in life partially
reverses aging!
Partial rejuvenation is available to you now!
This
is Only a Partial Rejuvenation
It should be emphasized that this is partial
rejuvenation in two respects.
(1) This rejuvenation will only subtract a decade or so
from your current physiological age, rather than taking you back to 18.
(2) Not everything gets rejuvenated. Unfortunately, you
won't look a decade or two younger.
When and How This Was
Discovered
In 1935,
Professor
Clive McKay at Cornell University conducted some
remarkable
experiments. He
found that if he underfed rats, but fed them very nutritiously, it increased
their life spans by as much as 40% by slowing their rate of aging. These lean
and hungry mice were smaller than fully fed mice, but were in excellent health
well after the normally fed rats had all died.
Later experiments have pushed these average and maximum
longevity numbers as high as 1.7 times that of fully-fed mice (see Dr. Roy
Walford’s, “Beyond
the 120-Year Diet”,
pg 48).
Since that time, this slower-aging phenomenon has been
extensively tested in animals ranging from single-celled protozoa to monkeys.
The first trial with macaque monkeys began in 1989 at the National Institutes of
Health in Bethesda, Maryland, with a parallel monkey experiment following close
behind at the University of Wisconsin. The underfed experimental monkeys
haven’t yet outlived their fully fed cousins because macaque monkeys live as
long as 40 years, but they are showing the same signs of youth-extension
exhibited by all of the other species that have been tested so far. Some human
volunteers have been following such a “caloric-restricted”,
optimal-nutrition (CRON) diet for more than 20 years, and, like the rest of the
animal kingdom, are exhibiting the indicia
of slower aging.
Caloric restriction is the only proven way of actually
slowing the rate of aging of a given species. Various strategies can increase the average
lifespan of a
species, by reducing death rates from common diseases. For example, the
reduction in infant mortality that occurred during the 19th and 20th centuries
through sterile procedures, professional obstreticians, and antibiotics boosted
the average lifespan in most societies. However, the maximum lifespan of
a species is unaffected by these interventions. Some people lived to a ripe old
age even during the Renaissance--e. g., Michelangelo, who died at the age of 89.
The life expectancy of a white male baby born in 1900-1902 was 48 years; his
life expectancy at age 30 was about 65 (taken from the United States Centers for
Disease Control National
Center for Health Statistics). If
he lived to the age of 30,
he
could expect 17 additional years of life
beyond his life expectancy at birth of 46 years.
By contrast, the life expectancy of a white male baby born in 2000 is projected
to be about 75; his life expectancy at age 30 is about 76.5. Living to the age
of 30 would give him only 1½ more years of life. This is a testimonial to the
reduction in early mortality that took place between 1900 and 2000. The life
expectancy of a 100-year-old white male born in 1900-1902 was 1.55 years;
the life expectancy of a white male in 2000 was about 2.2 years...
not very different.
So far, only caloric-restriction has been shown to sizably
increase the maximum lifespan of a species ("Beyond
the 120-Year Diet",
pg. 46), and so far, this has been demonstrated only in animal models. Of
course, it will take a century to demonstrate a 150- or 180-year-old human
through lifespan experiments. However, there a number of tests that can be
performed that point toward a slowing, and as you'll see below, a partial
reversal of certain aspects of aging ("Beyond
the 120-Year Diet",
Chapter 2, "Gauging Aging and Measuring Success").
One of the implications of this is that taking vitamin E or
Co-Q10 or curcumin may improve average lifespans but these nutritional
supplements don't
affect the maximum lifespan. The internal clock of aging continues to tick
inexorably, virtually unaltered by currently known health measures other than
the caloric-restriction effect.
Until the 1980’s, it was thought that, to be effective,
calorie restriction had to begin immediately after weaning in order to be
effective. This was because attempts to suddenly put adult animals on
calorie-restricted diets actually shortened their lifespans. However,
during the 1980’s, Walford
and Weindruch showed that if adult
mice or rats were given
time to gradually adjust to a lower calorie diet (the human equivalent of
several years), calorie restriction would work with them, too (see “Beyond
the 120-Year Diet”,
pg 48).
This is very important because it shows that calorie
restriction can be effective when started in adulthood as well as when begun in
infancy.
In 1999, Weindruch
and Prolla at the University of Wisconsin analyzed 6,347 genes in the
gastrocnemius muscle of old mice and found that about 1.8% of them (113 out of
the 6,347) changed substantially with age. They also found that about 70% of
these 113 genes (79 of them?) changed either undetectably or changed less with
aging in calorie-restricted mice than they did in mice fed ad libitum.
(30% of these genes were unaffected by caloric-restriction.)
A Bombshell!
In 2001,
Dr. Stephen
Spindler, Dr. Joseph Dhahbi, Patricia Mote, and their co-workers at the University of California – Riverside, under
the sponsorship of the Life Extension Foundation, put 34-month-old mice that had
been fully fed all their lives on a calorie-restricted diet for one month. At 34
months, these inherently long-lived mice were equivalent to extremely old
humans… perhaps 90 years of age, or more. Then at 35 months, the mice were
“sacrificed”, and their livers were subjected to a gene-chip analysis
looking for age-related changes. Simultaneously, a cohort of mice that had been
calorie-restricted throughout their lives were also sacrificed, were subjected
to gene-chip analysis, and the results compared to the gene-chip results of the
34-month-old mice. To Dr. Spindler’s amazement, the liver genes of the
short-term calorie-restricted mice showed about 70% of the anti-aging effects
exhibited by the liver genes of the mice that had been calorie-restricted since
weaning. In other words, these liver cells had effectively been partially
rejuvenated! This is clearly a matter of the greatest significance, since it
suggests that even old humans can be somewhat restored.
In their next study,
Dr. Spindler, Dr. Dhahbi, Ms. Mote, et al, (again supported by the Life Extension Foundation) switched, over a period of two
months, a cohort of long-lived 19-month-old mice “at the beginning of old age"
(at the human equivalent of 60 to 65) from a 10% caloric-restricted diet to a
54%-calorie-restricted diet, and then followed them throughout the rest of their
lives. (Note that the control group of mice were 10% caloric-restricted to
keep them from gorging on mouse chow.)
Once on the calorie-restricted diet for two months (a human-equivalent period of
about 6 years), the mortality rate for the
calorie-restricted mice dropped to about one-third what it is for fully
fed mice, and on average, the calorie-restricted mice lived the human equivalent
of 12 to 15 years longer than fully fed (actually, 10% caloric-restricted) mice. The longest lived 10% of these
mice lived 15 to 18 years longer than they would if they had been fully fed all
their lives.
Mortality rates in humans double in something like every 8
years. If you translate a reduction in mortality by a factor of 3 to the age at
which untreated mice would have had the same mortality rate, you arrive at
something like 13 years for the possible equivalent rejuvenation granted to 60-
to 65-year-old humans by late-in-life calorie
restriction.
This is great news for mice, but what does it do for the rest
of us?
Human
Experiments with Calorie Restriction
Some "longevinauts"
have been experimenting with calorie
restriction
for years now. In April, 2004, a
research team at Washington
University
published in the Proceedings of the National Academy of
Sciences,
the results
of the first study of calorie restricted individuals ever conducted, directed toward assessing
the atherosclerotic risks among them. The paper concludes,
"Based on a
range of risk factors, it appears that long-term CR has a powerful protective
effect against atherosclerosis. This is supported by the finding of a low
carotid artery IMT."
(The carotid IMT (Intima Media Thickness) was 40% less
than that of the controls.)
In a BBC
article
describing the study, one of the lead authors, Dr. Luigi Fontana, is
quoted as saying,
"These effects are all pretty dramatic. For the first
time, we've shown that calorie restriction is feasible and has a tremendous
effect on the risk of atherosclerosis and diabetes."
The Washington
University researchers observed that these 18 calorie restricted individuals are
at much lower risk for diabetes and cardiovascular disease than they were before
they started, and are at risk levels characteristic of those who are
"decades younger", and of those who will live to become centenarians. The levels of HDL vs.
LDL that are shown above should be high enough to clean out their arteries.
The Washington
University researchers
have initiated a prospective, follow-on study that will monitor these changes as
they occur.
It's significant that before they began calorie restriction,
the 18 individuals recruited for this study had possessed the same kind of
atherosclerotic risk factors as the control population (See Table 1 below)
The 15 men and 3 women in this study ranged in age from 35 to 82, with an average age of 58.
They had been calorie restricted for periods of time ranging from 3 to 15 years,
with an average calorie-restricted period of 6 years.
Table 1: Serial Measurements of Risk Factors for Atherosclerosis in CR Individuals
Parameter |
Controls |
Subjects |
1-Year CR |
Present |
% Change |
Body Mass Index (BMI),kg/m2 | 25.5 | 24.5 ± 2.6 | 20.9 ± 2.4 | 19.5 ± 2.1 | -20.4 % |
Total Cholesterol, mg/dl | 205 ± 40 | 194 ± 45 | 161 ± 31 | 157 ± 38 | -19.1 % |
LDL-C, mg/dl | 127 ± 35 | 122 ± 36 | 89 ± 24 | 86 ± 17 | -29.5 % |
HDL-C, mg/dl | 48 ± 11 | 43 ± 8 | 58 ± 13 | 65 ± 24 | +54.7 % |
Total Cholesterol/HDL-C Ratio | 4.5 ± 1.3 | 4.1 ± 1 | 2.8 ± 0.5 | 2.5 ± 0.4 | -39% |
Triglycerides, mg/dl | 147 ± 89 | 149 ± 87 | 112 ± 12 | 97 ± 8 | -34.9 % |
Systolic Blood Pressure, mm. Hg | 129 ± 13 | 132 ± 15 | 112 ± 12 | 97 ± 8 | -26.5% |
Diastolic Blood Pressure, mm. Hg | 95 ± 8 | 80 ± 11 | 69 ± 7 | 59 ± 5 | -26.3 % |
Table 2
(below) presents a few additional risk factors beyond those given in Table 1.
Table 2: Risk Factors for Atherosclerosis
Parameter |
Calorie-Restricted |
Controls |
P Value |
Total Cholesterol, mg/dl | 158 ± 39 | 205 ± 40 | 0.001 |
LDL-C, mg/dl | 86 ± 28 | 127 ± 35 | 0.0001 |
HDL-C, mg/dl | 63 ± 19 | 48 ± 11 | 0.006 |
Total Cholesterol/HDL-C Ratio | 2.6 ± 0.5 | 4.5 ± 1.3 | 0.0001 |
Triglycerides, mg/dl | 48 ± 15 | 147 ± 89 | 0.0001 |
Triglycerides/HDL-C Ratio | 0.8 ± 0.3 | 3.5 ± 2.8 | 0.0001 |
Systolic Blood Pressure, mm. Hg | 99 ± 10 | 129 ± 13 | 0.0001 |
Diastolic Blood Pressure, mm. Hg | 61 ± 6 | 95 ± 8 | 0.0001 |
Fasting Glucose, mg/dl | 81 ± 7 | 95 ± 8 | 0.0001 |
Fasting Insulin | 1.4 ± 0.8 | 5.1 ± 2 | 0.0001 |
Hi-sensitivity C-Reactive Protein, mg/ml | 0.3 ± 0.2 | 1.6 ± 2.2 | 0.001 |
With 20/20
hindsight, this seems to me to be inherent in Dr. Roy Walford's book, "Beyond
the 120-Year Diet" (pg. 44). He certainly doesn't claim in his book that caloric
restriction begun later in life will subtract 15 years from your physiological
age, and 15 years is a just a saddleback guess, anyway. However, he lists the
following average decreases in health-related biomarkers that occurred among the
eight members of the Biosphere II project six to eight months after they were
forced to go on a CRON (Caloric-Restricted with Optimal Nutrition) diet
by
an inability to grow enough food during the two years they were confined within
Biosphere II.
Like the 18 participents in the Washington University study, whose
age-related biomarker changes are summarized in tables 1 and 2 above, they also
experienced major improvements in health-related indices, as shown in Table 3.
Table 3: Effects of 6 to 8 Months of
Caloric Restriction Upon the 8 Biosphere II Team Members
Test or Determination | Average Percent Change |
Weight | 14 % decrease |
Systolic blood pressure | 18% decrease |
Diastolic blood pressure | 28% decrease |
Blood sugar | 21% decrease |
Cholesterol | 36% decrease |
White blood cell count | 31% |
Insulin | 42% decrease |
T3 (a thyroid hormone) | 19% decrease |
Renin | gradual decrease |
Glycosated hemoglobin | gradual decrease |
Triglycerides | gradual decrease |
Calorie-Restriction Appears to Partially Reverse Aging, As Well As Slowing It
Down.
If caloric-restriction merely slowed the rate
of aging, there would be no immediate change in these age-related biomarkers.
Instead, they would simply deteriorate more slowly in the future. However, these
results suggest what gene-chip
studies imply...
that there is actual partial rejuvenation taking
place.
The Bottom Line? It Doesn't Matter
Whether Caloric-Restriction Reverses or Slows Aging If It Greatly Improves Your
Health
It will be decades before we can be certain that
calorie-restriction does in humans what it does for animal models: slow the rate of aging and extend both the average and the
species-maximum lifespan. But regardless of whether or not caloric restriction increases
the lifespan, it clearly
markedly improves current health, and this alone is worth the
price of admission. The point is that CR hugely improves cardiovascular and
glucose management parameters, and, perhaps, no longer needs to be justified on
the basis of proven "youth extension". The health benefits alone
should pay its freight.
The Washington University studies were directed toward
cardiovascular health, but that's only the tip of the iceberg. Studies in mice
show that lifelong calorie-restriction greatly delays the onset of cancer, and
to a degree, eliminates cancer altogether. (Since cancer chances in humans tend
to double every 8 years, delaying cancer by 8 years would equivalent to reducing
the risk of cancer by a factor of 2.) Calorie-restriction also greatly reduces
the risks of diabetes, arthritis, and mental decline. These "Methuselah
mice" tend to be vigorous and disease-free right up until the end. In many
cases, it's hard to tell what killed them.
You've Probably Already Experienced This and
Didn't Know It!
There's nothing mysterious about caloric
restriction. You've probably already experienced this. It happens whenever you
lose weight over an extended period of time... e. g., with Weight Watchers. What
hasn't been known is what effect this was having upon us.
Beyond that, losing weight is the hardest part of the job.
You can eat a lot more on a maintenance diet. (The idea that most people can't
manage calorie-restriction seems silly to me. Losing weight is a lot harder than
keeping off your weight.)
Caloric Restriction Is Just a Fancy Name for
Slimming Down, and Then Not Eating Too Much
Calorie
restriction is just a fancy name for losing weight down to slim and trim, and
then trying to eat just enough that you don't lose any more weight, rather than
trying not to eat so much that you put on more weight. Must of us try to eat as
much as we can without gaining weight, but for me at least, that never worked
very well. Now and then, I'd eat a little too much, and over time, my weight
would creep back up again.
How slim and trim? CRONers (Calorie-Restriction; Optimal
Nutrition) typically have body mass indices (BMIs) ranging from
19 to 22. For a six-foot guy, that represents a weight between 140 and 162. For a five-foot, five-inch woman, that would be
114 pounds to 132
pounds.
It's important any time you're on a diet that you be careful
that you get all the necessary nutrients so that you're not malnourished. This
can be tricky when you have a low caloric intake. Also, eating right and living
well can add, possibly, as much as a decade to your lifespan independently of
caloric-restriction.
It's also important that you lose weight slowly... no more
than a pound a week, and preferably less.
Until the 1980’s, it
was thought that, to be effective, calorie restriction had to begin immediately
after weaning in order to be effective. This was because attempts to suddenly
put adult animals on calorie-restricted diets actually shortened their lifespans.
However, during the 1980’s, Walford
and Weindruch showed that if adult mice or rats
were
given time to gradually
adjust to a lower calorie diet (the human equivalent of several years), calorie restriction would work with them,
too (see “Beyond
the 120-Year Diet”,
pg 48).
This ties in with the Walford and Weindruch study that showed
that caloric restriction could prolong life in adult animals only if it were
introduced slowly.
One of us (Bob) has been on a calorie-restricted diet since,
September, 2003, losing 32 pounds (down to 128 pounds) in the process. (That's
four gallons of fat I'm not having to lug around with me wherever I go.) Think
how you'd fell if you had to do everything day and night carrying four gallons
of milk around with you. And then imagine what it would mean to be able to take
off that four gallons of water. Think how light on your feet you'd feel! And
I'm feeling great! I've gone back to running
several miles a day... something I never thought I'd be able to do again.
I'm running as far and as fast as I did 20 or 30 years ago. (Instead of being
hard on my joints, it seems to have greatly improved them.)
Losing weight by 20% (32 pounds divided by 160 pounds) means
that I automatically need 12% fewer calories because there isn't as much of me
to feed. The rest of a 30% or 40% reduction caloric intake comes from
improvements in energy conversion efficiency that your body delivers if food is
tight. It wastes less energy generating body heat than it does when you're
flooded with food.
It's also important to know that body fat produces hormones
that, among other effects, make you hungrier.
I certainly didn't plan to go on a calorie-restricted diet
when I started last September, but after the annual Lucullen feast at Fred
and Kay
Vaughan's house in August, it was time to lose a little weight. I also wondered
whether my hypertension could be a consequence of the fact that I had put on
weight in my late twenties. If I lost weight down to something like what I
weighed in my twenties, would my blood pressure normalize? After crawfishing for
a few weeks, I finally started losing weight, and then I realized, "Hey!
I'm on a caloric-restricted diet! I mean, if you're losing weight, you're on a
calorie-restricted diet, right?"
I had planned to get my annual physical in April or May to
see what this calorie-restriction had done to my bloodwork, but in February, my
family practitioner called me in for a physical. When the bloodwork came back
some of the numbers were surprising. My HDL level, which had never been higher
than 51 before, was 71. My triglycerides, which were usually in the 80's, was
54. My fasting blood sugar was 81. My total cholesterol was higher than I
expected at 180, but I had been caught off-guard, and had eaten a large egg and
some chicken less than a day before the test. (I'm quite responsive to
exogenous fat and cholesterol.) My LDL was 98.
My blood pressure has also dropped dramatically, though not
quite down to the 110/70 level I'd like. (It was 114/67 when I took it this
afternoon.)
These numbers agree nicely with the averages in the
Washington University study, and were achieved only a few months after I started
my diet. This suggests to me that we may be able to test the effectiveness of
different regimens with humans in only a few months time.
I decided I would try to keep my calories down and run
calorie-restricted after I reached maintenance weight. Maintaining your
weight on a calorie-restricted is, of course, easier than losing weight on a
diet.
Many of us don't get hungry on caloric-restricted diets. I
want to emphasize that I don't get hungry. Part of the trick is to find
low-calorie foods that are filling and nutritious. Another part is probably
avoiding the starch/sugar roller-coaster that drives your blood sugar into a
diabetic range and then allows it to crash to hypoglycemic levels. Still another
may be the fact that you're getting a high level of nutrients, along with
adequate "good fats" and protein. (More on that farther along in
this article.)
A little later in this installment, I'll detail my tricks for
feeling full and satisfied, and for avoiding hunger.
This calorie restriction response is more than just slowing
the rate of aging by burning life's candle slower. One explanation is that it's
an evolutionary program conserved across the plant and animal kingdoms
allowing organisms to switch during periods of environmental stress from a modus vivendi optimized for
reproduction to a mode of existence optimized for survival. Changes are
triggered at the cellular level increasing DNA repair and partially reversing
numerous other age-related declines. Once the environmental stress has passed,
the organism reverts to an existence aimed at maximum reproduction.
Many fashion models
and Weight Watchers are probably on caloric-restricted diets.
There is a wealth of valuable information on the Calorie
Restriction Society website.
My Experience with Restricting Calorie
Intake
The first consideration is that we all must and do practice
calorie restriction. If we didn't we'd weigh 1,000 pounds. It's just a question
of where we draw the line. I've been restraining myself for decades now, having
dieted to lose weight for the first time in 1973. Since then, I've had to fight
the battle of the bulge for 30 years, putting on a few pounds over the holidays
and dieting to lose them as a part of my New Year's resolutions. But for most of
us, it's a constant struggle. The surprise here is that, at least for me, it's
easier to stay in this calorie-restricted mode than it is for me to guiltily try
to hold down my eating so that I don't put on weight. Part of my problem has
been that I tend to "pig out". It's not safe to leave me in the same
room with a half gallon of Breyer's butter pecan or a Sbarro's pizza, so I've
learned not to buy them. But with me, the more I ate, the more I wanted. I'd get
started with something good at bedtime and I wouldn't want to stop. Also,
sitting here all day in front of the computer, with a refrigerator and a
microwave handy is an open invitation to pigdom. But part of the remedy is to
find foods that are low in calories, and yet filling. (Some of the "CRONies"
use guar gum and other fillers to derive a feeling of fulness that lasts for
more than a few minutes.)
I'm chewing on something all day long. It's just that what
I'm chewing on (an almond at the moment) doesn't have many calories and is
good for me. You can eat all the salads you want. Low-calorie vegetables like
broccoli, spinach, cabbage, tomatoes, and lettuce can be eaten in profusion.
Once you've experienced how good you feel in a lower-weight,
optimal nutrition mode, you won't ever want to want to go back to your old
lifestyle. At age 75, I run everywhere I go. A year ago, I was having trouble
climbing our stairs. Since I lost weight, I no longer get headaches or any other
kinds of aches. I don't know when I last had a cold or the flu. I'm energetic
from breakfast to bedtime (if I've had a full night's sleep).
The
ON Part of a CRON (Caloric-Restricted, Optimal-Nutrition) Diet
Because people on weight-loss diets are taking in fewer calories than those who
are eating all they want, it becomes harder to get the recommended daily
alowances and proper balance of various nutrients. One very important point
to observe if you're thinking about going on a diet is that you're absolute
protein intake must stay the same. (Protein turnover actually increases when
you're on a diet.) Similarly, it's important to get enough of, and the right
combination of essential fatty acids. It's the carbohydrates that must be
reduced, while the protein and exxential fatty acids remain the same as they
were before you started dieting. (This means that the percentages of protein and
fat will rise as a fraction of total caloric intake.)
How important is optimal nutrition? One
recent study of California Seventh-Day Adventists published in the july 9,
2001, issue of the Archives of Internal Medicine reported that the expected ages
at death for those surviving to age 30 was 81.2 years in men, compared to an
average age of 73.9 for non-Adventist California men surviving to age 30, and
was 83.9 years in Adventist women surviving to age 30, compared to 79.5 years
for non-Adventist California women. This is an extra 7.3 years for the Adventist men
and an extra 4.4 years for the Adventist women. Adventist men who were
vegetarians have a life expectancy of 83.3 years, and vegetarian women have a
life expectancy of 85.7 years, or 9.5 years and 6.1 years longer, respectively, than the
average Californian. Comparing the average age at death for non-vegetarian
Adventists (82.5) with the average age at death for vegetarian Adventists
(84.5), we find that vegetarians live an average of 2.0 years longer than
non-vegetarian Adventists. And these are averages that include various kinds of
congenital conditions, and varying degrees of dietary conformity. The paper concludes,
"Our results strongly suggest that there is real
potential for other Americans to also extend their life expectancy by 5 to 10
years with relatively simple behavioral choices."
These life expectancy extensions refer to average lifespans
rather than to the lifespans of the longest-lived among them.
Of course, laboratory mice live out their lives in
controlled, protected environments. They don't ride Harleys, smoke two packs a
day, and subsist on beer and hot dogs, so their average lifespans are probably
closer to their maximum lifespans than is the case with an across-the-board
human population that includes some high-rollers.
The
Diabetic Drug Metformin Appears to Produce Many of the Effects of Caloric
Restriction
Don't think you're up to caloric restriction? How about a
pill that will accomplish the same thing?
Using gene chips, Dr.
Spindler and his colleagues screened several drugs for their potential as
"caloric-restriction mimetics"... chemicals that would trigger the
caloric-restriction response in organisms. They found one in a glucose
management drug called metformin that has been in use for 40 years
"The glucoregulatory pharmaceuticals and the combination
of two of these pharmaceuticals produced a significant number of changes in
hepatic gene expression identical to those produced by long-term and/or
short-term CR. The most extensive overlap with CR was obtained from metformin.
The gene expression changes common to metformin and CR were associated woth
xenobiotic metabolism. The changes are coinsistent with enhanced apoptosis and
protein turnover, and reduced tumor incidence and cellular stress. These results
suggest that metformin is a potential CR-mimietic. Others have shown that
phenformin, a glucoregulatory pharmaceutical structurally and functionally
similar to metformin, extends the lifespan of mice by 23%, and reduces cancer as
a cause of death from 80% to 20%. Others recently have presented preliminary
evidence that metformin extends the lifespan of rats. Therefore agents that
reproduce the long-term CR signature in microarray assays are candidate CR
mimetics."
Metformin is a safe drug as drugs go, but it shouldn't be
used by individuals with liver or kidney problems.
Dr. Spindler is currently running a lifespan study on
metformin to check the preliminary results obtained by Dr. George Roth at the
National Institute on Aging. (Dr. Roth found a lifespan extension of 20% for
mice on metformin.)
Resveratrol May Be the Ideal Caloric
Restriction Mimetic
Resveratrol is the caloric-restriction trigger announced by
Drs. David Sinclair and Konrad Howitz last August that triggers the
caloric-restriction response in yeast and in fruitflies and roundworms. So far,
studies in humans of its safety and efficacy in eliciting the
caloric-restriction response are, to our knowledge, not yet available.
Aging Research Is On a Roll
Research in the conquest of aging has come to a rolling boil. On
June 2, 2004, MIT's Lenny Guarente and his associates published a paper
in Nature that ties the Sirt1 gene and its associated protein to the storage vs.
the burning of fat in the body. When the Sirt1 protein senses short-term
famine--through extended periods of low blood sugar?--instead of storing fat, it releases fat to be
burned by repressing the PPAR-gamma (Peroxisomal-Potentiating
Activator Receptor-gamma) gene that controls fat .
What kind of market do you think there would be for a pill
that would allow you to eat all you want without getting fat, and
simultaneously, greatly improve every aspect of your health as well as extending
your "youthspan" by 10-to-15 years? Elixir
Pharmaceuticals), two of whose founders are Dr. Guarente and Dr. Cynthia Kenyon, is a promising
future source of such a pill.
Also on June 2, 2004, a group of researchers from the
Imperial College in London reported on a fat regulation gene called RIP140 that,
when blocked, reduced fat levels by 20% in mice (). It blocks the expression of uncoupling protein 1 UCP1) that, when blocked,
causes the body to burn more calories to generate body heat rather than storing
these calories as fat.
On June 4, 2004, a group of researchers at Brown University
reported that reducing insulin levels in the fat cells of fruit flies near their
brains reduced insulin levels throughout their bodies and extended their
lifespans by 50%.
The nub of all this is that there is a ferment of aging
research activity around the world. There is now a number of journals dedicated
to aging research, and numerous papers are appearing in mainline journals such as Nature, Science, and the Proceedings
of the National Academy of Sciences.
How
to Lose Weight and Remain Caloric-Restricted
Just about everyone would like to weigh less, and most people
have probably lost weight on a diet. And it's a lot harder to lose weight on a
diet than it is to maintain your weight once you've lost it. So how do you do
it?
First of all, you probably need to know that your two genial
co-authors enjoy food as much as anyone. With one of them, it isn't safe to
leave a half gallon of Breyer's low-fat, butter pecan, frozen yogurt or a
Sbarro's pizza alone in a room with him,.so it's not that your genial authors
are cut from different cloth than you.
In the February, 2003, issue of "Gift of Fire",
Fred Vaughan writes about how he and Kay lost weight and kept it off. He
mentions that mindset is very important. It entails a lifestyle change. It
needn't visit any hardship upon you, given a change from carelessly
squandered calories to carefully chosen ones. And once you've lost weight,
you'll never want to go back to being heavy again.
As we grow older, we all tend to become Type II diabetics:
our cells, overloaded by a modern lifetime of sugar-converted starches,
become desensitized to insulin. Our pancreases make more and more insulin until
finally, they "burn out". But long before frank diabetes rears its
ugly head, pre-diabetes is taking an invisible toll, wreaking almost as much
havoc as diagnosed diabetes. Beyond that is the fact that energy
metabolism seems to play a central role in aging. And aging is a process of
steadily elevating your risk of developing cancer, cardiovascular diseease,
cerebrovascular disease, diabetes, Alzheimer's disease, Parkinson's disease,
osteaoporosis, arthritis, and other ills that flesh is heir to. Aging is a
consummation devoutly to be avoided. And the time to avoid it is early on,
before you're hospitalized. It's always a better idea to visit your friends and
relatives in hospitals rather than have them visit you there.
For a long time, it was thought that it's healthier to put on
a certain amount of weight as you grow older, and the healthiest weight profile
is a BMI (Body Mass Index) of 22 to 24 (162 to 177 pounds in a six-foot-tall
man, or 128 to 140 pounds in five-fott four-inch woman). But these survey
numbers failed to take smoking and occult diseases into account. The National
Institute of Health's (NIH) Nutrition Committee and the Centers for Disease
Control (CDC) have concluded that the weights associated with greatest longevity
are below BMI's of 22 to 24. In the National Cancer Institute's long-term
Nurses' Study of 110,000 women, the lowest mortality rate was found with BNI's
below 19 (from Dr. Roy
Walford’s, “Beyond
the 120-Year Diet”,
pg 48). So thin is in, and stout is out.
Okay. You want to lose weight, but it's hard to do. The urge
to nibble is tugging at you all day long. And what do you do when you go out to
eat? If you don't get enough to eat, will you get hungry later in the day, and
maybe headachy, weak, and light-headed? And if you don't eat enough now, how
will you get anything to eat in the middle of the afternoon, or before bedtime?
And the junk in the coin machines is pretty bad.
My
(Too-Rapid) Weight
Loss Protocol:
Breakfast:
Cup of hot chocolate:
1
bag of green tea in a mug of cold water heated for 2¼ minutes in the microwave.
Stir a bit to get the tea out of the tea bag, and then add 1 heaping
teaspoon of unsweetened baking cocoa*
and two packages of Splenda natural sweetener. Lemon juice to taste (not many
calories).
Eggbeaters,
with chopped onion, 3 chopped black olives, and 20-30 calories worth of lean ham
or chopped-soy sausage, with rosemary&
sprinkled over it (<100 calories). Half a piece of thin-sliced, five-grain
toast, with "Promise" fat-free "margarine (25 calories?).
Snacks:
I
gnaw on almonds one at a time all day long (12 to 15 a day). I may also gnaw on
a slice of low-fat (Louis Rich) or fat-free (Jenny O) bacon (35 calories) eaten
a morsel at a time that is very flavorful and chewy. It works like chewing gum
that you can eat after you've extracted all the flavor..
Lunch:
Thin
slice of Monterey Jack soy cheese. Two dozen or so frozen blueberries. (Want
more lunch? I lost weight too rapidly. You may want to add in a tossed salad and
a low-calorie half-sandwich, or some other Weight Watcher's equivalent.)
Afternoon
snack:
Another
cup of green tea/hot chocolate. Almonds/Bacon.
8
- 9 p. m. supper
Cup
of hot chocolate,
and
Small bowl of slow-cooked oatmeal, with 1 packet of Splenda, 2-to-3 frozen
strawberries, and 12-to-20 frozen blueberries, irrigated with soy milk, or
modest serving of microwaved spinach or microwaved broccoli, cauliflower, and
carrots, covered with pizza sauce#,
and sprinkled with rosemary and turmeric%.
Half-sandwich of salmon salad (salmon, fat-free mayonnaise, pickle relish and
chopped walnuts), using one slice of thin-sliced, five-grain bread, with fresh
or microwaved spinach on it, or hamburger made with 96% fat-free ground beef,
and onion, tomato, and fat-free mayonnaise), with fresh or microwaved spinach on
it.
Cheats:
Several
Orville Redenbacher sour-cream-and-onion popcorn disks; 1 Brown Cow Junior
sugar-free ice cream bar (70 calories); some Ghirardelli bittersweet chocolate
drops. (The Ghirardelli chocolate drops are one-calorie each and don’t have
trans fats in them.)
* Cocoa
from a health food store is available that is extracted without alkali and
that allegedly retains more of the polyphenols that are supposed to be so
good for you. Major manufacturers such as Nestle's are said to be preparing
to market, during the summer of 2004, cocoa that has more of the natural
polyphenols in it.
& Rosemary is said to be a COX-2 inhibitor like
the latest arthritis drugs Celebrex
and Vioxx. (See "Cancer
Fighters in Your Spice Rack", http://www.medicomm.net/Consumer%20Site/hc_nutrition/hcn_a2.htm.)
# for
lycopene
% for curcumin
Cheats:
Several Orville Redenbacher
sour-cream-and-onion popcorn disks.
1 Brown Cow Junior sugar-free ice cream bar (70 calories)
Several green-wrapped chocolate mints that are found at
restaurant checkout counters.
1/16th apple, with cinnamon. Cinnamon contains the "phytoinsulin"
methylhydroxy chalcone ploymer (MHCP)*
that, in very small doses... less than 1/2 teaspoon day... in
volunteers aged 40 to 65, lowered blood sugar by 18% to 29%, triglycerides 23%
to 30%, LDL 7% to 27%, and total cholesterol 12% to 26%. The researchers found
no advantage in eating more than the minmum dose. Cinnamon contains oil-soluble
components that can accumulate in the body as well as water-soluble components.
However, the researchers advised that the minimum dose would probably cause no
problems if it accumulated at that minimum rate.
* - http://www.ars.usda.gov/is/AR/archive/jul00/cinn0700.htm,
http://www.ars.usda.gov/is/AR/archive/apr04/cinnam0404.pdf,
http://gsearch.ars.usda.gov/search?q=cinnamon&btnG=Go%21&restrict=iapreview&filter=0&as_sitesearch=www.ars.usda.gov&site=iapreview&ie=&output=xml_no_dtd&client=iapreview&lr=&proxystylesheet=iapreview&oe=
http://www.ars.usda.gov/is/np/fnrb/fnrb0104.htm#burn,
http://www.ars.usda.gov/research/projects/projects.htm?ACCN_NO=404780&fy=2002
-----------------------------------------------------------------------------------------------
* - for lycopene
** - as a COX-2 inhibitor
*** - for curcumin
The Maintenance Diet
The maintenance diet is much more accommodating, with spinach
and/or broccoli mixed in with the scrambled eggbeaters and with any meats. (You
don't much taste the broccoli or spinach when it's mixed in with The salmon
salad (salmon, a little fat-free mayonnaise, and some pickle relish and/or other
chopped garnish) is included for its omega-3 fatty acids and its taurine
content. The occasional hamburger is food for the soul, and is included because
our northern ancestors must have evolved to eat lean red meat like this.
Of major importance are the almonds to gnaw upon to keep the
wolf away from the door. An alternative is a slice of low-fat (Louis Rich) or
fat-free (Jenny O) bacon eaten a morsel at a time that is very flavorful and
chewy. It works like chewing gum that you can eat after you've extracted all the
flavor.
* - Broccoli, turmeric, garlic, and alpha-lipoic acid restore cellular levels of
the main cellular defense system (glutathione perioxidase and Nrf2) to those of
young animals.
More
"Tricks of the Trade":
If you're going to eat starches--baked potatoes, sweet
potatoes, fruit, etc.--eat a little at a time, and sprinkle a little cinnamon on
them. That way, you won't be subject to sugar surges. If anyone asks you why
you're doing what you're doing, you can tell them that you've been advised to be
a little careful about your sugar. If they ask about the cinnamon, that might be
a good time to tell them about the U. S. Department of Agricutlture's pending
patents on cinnamon compounds to lower blood sugar, cholesterol, and
triglycerides. They might be glad to know about that.
Spacing out carbohydrates over the day, and emphasizing
complex carbohydrates over starches is important because it keeps you off a
blood-sugar roller-coaster, and helps keep you from getting hungry. Almonds and
walnuts are good because they contain some "good" fats, along with a
lot of other nutritious biochemicals.
Protein and "good" fats are filling, maybe because
they satisfy the body's needs for such nutrients.
It's worth noting that natural foods contain tens of
thousands of different proteins... more than there are genes in the plant's or
animal's genome. Most of these are present in trace amounts, but when you eat an
egg or a seed, you're eating an enormous number of different biochemicals. This
is why "enriched" food is something of a joke.
OK.
But what happens when you're at work?
Generally, you can make hot chocolate at your desk. I used
one of these little water-heating coils to heat water at my desk. For lemon
juice, if there isn't a refrigerator happen to store bottled lemon juice, you
may be able to get the kind of lemon packets that fast-food restaurants use for
tea. If you're in a meeting all morning (God forbid!) and you're dependent upon
the coffee machine, you might be able to take
What happens when you observe these shibboleths? One of the
consequences is that you don't need to worry about getting hungry or
light-headed in between meals. This means that usually, you don't have to eat
junk in greasy-spoon restaurants if the crowd goes there for lunch. Also, almost
all restaurants have choices you can make that are healthy. Of course, there
could be circumstances--for example, when you're traveling-- in which you have
to eat enough to stave off hunger later on, and there may be situation in which
you have to buy something like pretzels out of a coin machine.
One of us generally drinks water at restaurants, sometimes
adding extra lemon and Equal to turn it into a sugar-free, calorie-free
lemonade.
What
About the Social Aspects of Caloric Restraint?
Several members of the Caloric Restriction Society have
commented upon the awkward moments when they're eating out with a pot-bellied
crowd. But everybody knows they should be on a diet, and everybody this side of
Antarctica knows that the world is tooling up to combat a global pandemic of
gluttony and obesity. The remark, "I'm on a diet." should lay to rest
questions about why you aren't entering into the Roman orgy. If not, you could
probably say something like, "What you've got looks delicious!"... i.
e., I'd eat it, too, if my doctor didn't have me on such a strict diet. One
approach is simply to laugh along with any teasing you get about your dainty
appetite. But it's cool not to eat too much.
Most people aren't that interested in what you're eating, and
when you get right down to it, it isn't any of their business, any more than
that what they eat is any of your business.
Of course, if you're at someone's house and the hostess
serves you a generous helping after you've said that you re on a diet and can't
eat much, I'm not sure what the proper etiquette would be. At worst, you can go
ahead and eat it. After all, you gave it your best shot.
Shadows
of What Is to Come
Research
directed toward the conquest of aging has come to a rolling boil. On June 2,
2004, MIT's Lenny Guarente and his associates published a paper in
Nature that ties the Sirt1 gene and its associated protein to the storage vs.
the burning of fat in the body. When the Sirt1 protein senses famine, instead of
storing fat, it releases fat to be burned, turning on the caloric-restriction
response in mice. (Thanks to Brian Schwartz for pointing this out.)
A
race is on to find pills that can trigger the full caloric-restriction response.
What kind of market do you think there would be for a
pill that would allow you to eat all you want without getting fat, and
simultaneously, greatly improve every aspect of your health, as well as
extending your "youthspan" by 10-to-15 years? Also, Harvard is
patenting a pill that may afford us the longevities of centenarians. These
mechanisms may be independent, suggesting even greater
“youthspans”.
On June 4,
2004, a group of researchers at Brown University reported that reducing insulin
levels in the fat cells of fruit flies near their brains reduced insulin levels
throughout their bodies and extended their lifespans by 50%. (Thanks to Brian
Schwartz for this input, also.)
Dwarf mice live
about 40% to 70% longer than full-size mice. Dwarf mice on CR live 25% longer
than dwarf mice on unrestricted diets, implying that part
of the increased longevity of dwarf mice involves gene changes that are
independent of CR.
The crux of all this is that there is a ferment of aging
research activity around the world. There are now a number of journals dedicated
to aging research, and numerous papers are appearing in mainline journals such
as Nature and Science.
Animals
have been discovered that show no signs of aging. For example, the calico
species of rockfish has a lifespan of the order of 12 years, while the
rough-eyed rockfish reaches at
least 205 (see reference 31), and shows no signs of aging even at
this age. Recently, the red sea urchin has also been shown to reach at least 200
with no signs of aging. Of course, these species may actually age if they live
long enough, but there's certainly a huge difference in rates of aging between,
for example, the calico rockfish and their kissing cousins, the rough-eyed
rockfish. Presumably,
the differences between the calico rockfish and rough-eyed rockfish are minor.
Beyond
this is the fact that life has descended in an unbroken chain for more than a
billion years without ever growing old. When old sperm cells, stem cells, or
even old somatic cells are planted in enucleated egg cells for cloning, the
resulting zygote is totally rejuvenated. Nature evidently has a trick up her
sleeve for completely rejuvenating zygotes before meiosis begins. If we can find
a way to invoke this cellular refurbishment in the differentiated cells of our
bodies without de-differentiating them, and without each of them trying to turn
into embryos, we may have a means of fully rejuvenating ourselves. That’s a
big “if”, but even without that, there’s reason to suspect, from Dr.
Spindler’s studies and from other
leads, that genes control aging, and that it’s possible to reverse aging
through genetic manipulation.
A combination of drugs might do what metformin does only partially.
It's been
observed many times that each age has its paradigms. One of our paradigms is
that, sooner or later, everything wears out. Cars, people, plants... even rocks
wear down. But it turns out that this isn't always true. Plants like the quaking
aspens and the box huckleberry, or the baobab tree that spreads by
runners, don't
seem to ever grow old.
Some liverwort clumps may be millions of years old. “Wear-and-tear”
theories of aging have been intuitively
popular, but life is digital and self-repairing, and evidently, may be
potentially capable of total self-repair. (We are dealing with technology that,
if we didn’t have living organisms to serve as templates, is probably at least
a century or two beyond today’s nanotechnology.)
I believe that some of you who are reading this may be alive and well in
2100.