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).
I
f 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.  

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Fig. 3. Representation of the results of longevity studies conducted by BioMarker. The black line shows the life span of control mice who consumed a normal number of calories. The red line shows the life span of mice subjected to caloric restriction starting in old age. The blue line shows the life span of mice subjected to caloric restriction, starting very early in life. A major finding is that CR extended the remaining life span by the same proportion in both experimental groups.

    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
(Non-CR)

Subjects
Pre-CR

1-Year CR

Present
Time

%
  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.

image
Fig. 4. The ability of drugs to mimic the gene expression effects of caloric restriction. BioMarker scientists found that metformin was most effective at reproducing the gene expression biomarkers of CR. Metformin's ability to do so is represented at 100% by the lowest bar in the chart, with the other drugs represented according to their lesser ability to mimic CR relative to metformin.

    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.

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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.)

1/16th apple, with cinnamon[1]. Cinnamon contains the "phytoinsulin" methylhydroxy chalcone polymer (MHCP)[2] that, in very small doses... less than 1/2 teaspoon a 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 benefit to eating more than the minimum amount of cinnamon.
 

*   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

[1]            http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14633804&dopt=Abstract

[2]             http://www.ars.usda.gov/is/AR/archive/jul00/cinn0700.htm



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.htmhttp://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. 

image
Fig. 5. Survival plots of Ames dwarf (DF) and normal (wild-type, WT) mice fed ad libitum (AL) or restricted to 70% of normal calorie intake (calorie restriction, CR). (Reproduced from Bartke A, Wright JC, Mattison JA, et al. Extending the life span of long-lived mice, Nature, 414:412, 22 Nov. 2001)

       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.

      An expanded version of this article, along with active hyperlinks to references, can be found at http://hiqnews.megafoundation.org/Longevity_Index.htm.