Two Important Papers on Aging

February 15, 2006

Bob Seitz


(1)  Calorie Restriction Improves Diastolic Function
    The Washington University researchers who reported in a National Academy of Sciences paper in April, 2004, that a complement of calorie restricted subjects were exhibiting dramatically improved cardiovascular risk profiles has followed up that original paper with a follow-on study in the Jan. 17, 2006 Journal of the American College of Cardiology. This paper shows that the diastolic functions of the hearts in 25 calorie-restricted individuals was, on average, about 15 years younger than that of  fully fed matched controls. Diastolic function is a primary marker of aging, and is a measure of the elasticity of the heart.

(2)  Resveratrol Fed to Killfish Extends Their Maximum Life Span 59%
(2)  In the fall of 2003, Dr. David Sinclair at the Harvard Medical School reported that his team had identified resveratrol, a stilbene peptide found in red wine and peanuts, as the mimetic triggering the caloric restriction response in yeast. Administration of resveratrol to yeast had increased its maximum life span by 70%. At the time, a research group at the University of Connecticut was measuring a life span extension of about 15% in resveratrol-fed roundworms (C. Elegans). It was hoped that resveratrol might be the magic "diet pill" that could confer the benefits of calorie restriction without restricting calories, allowing chubby couch potatoes to have their cakes and eat them, too. However, it was quickly shown that resveratrol is almost immediately metabolized in humans, and it was argued that it would be ineffective as a calorie restriction mimetic. Now, researchers at Avila University in Italy, in a paper in Current Biology, have shown that fish fed resveratrol had a maximum life span 59% longer than a normally fed control group. Apparently, ingestion is an effective way to administer resveratrol to animals. Surprisingly, the shape of the survival curve for the fish suggests that resveratrol extends life spans through a different mechanism than calorie restriction. Calorie restriction moves the survival curve to the right without changing its shape. Resveratrol stretches the survival curve. There are indications that resveratrol potentiates the body's own antioxidant defenses: superoxide dismutase, catalase, and glutathione perioxidase. If so, this will mean that resveratrol isn't the long-sought calorie-restriction mimetic. But the good news is that its life extension might be added to calorie restriction, so that instead of an additional 15 years afforded by calorie restriction, one might be looking at 25 or 30 years of additional good health and longevity.
    In any case, resveratrol looks like a worthy addition to life extension strategies. 
   One note of caution:  The authors of the resveratrol paper point out that there was an initial increase in morbidity in their fish. They suggest that resveratrol might be somewhat toxic. However, those of us who have taken resveratrol (really, red wine extract) have encountered no toxic effects. Presumably, red wine extract should be safe in moderate doses. however, this caveat should be mentioned.

    If resveratrol and calorie restriction do act independently and if they do increase life span additively, then the long-awaited, over-the-waterfall chain reaction in the conquest of aging might possibly be at hand.. It's certainly too early to break out the balloons and the party hats, but this could possibly be remembered some day as an historic moment.

 

    Is it really happening? Are we really going to see people living 15 or 20 years longer? 
    First, a word about life expectancies.
    The present average life expectancy for a guy at birth  is about 75, and the average life expectancy for a girl at birth  is about 80. That's the overall average, and it includes the people who drink, smoke, and drive motorcycles the wrong way down one-way streets (and the unlucky souls who are driving the right way who crash into them). A better indicator of life expectancy might be that of life expectancy at some elevated age. For example, the life expectancy at 76 is 11 years, up from 10 years a century ago. 


By contrast, the average life expectancy for people born in 1900 was about 47, although most of the 


 Stanford University's Dr. Shripad Tuljapurkar has just predicted at the annual meeting of the American Association for the Advancement of Science that by 2050, the retirement age will have to be raised to 85. Given that this is about 45 years away, and that the average life expectancy has been increasing by ¼ year per year, that's not an unlikely scenario. (¼ year per year would lead to a retirement age of 78 or 79 by 2050  even without any "breakthroughs" in anti-aging technology.) Yesterday, w woman who lived about 50 miles (80 kilometers) from here died at the age of 116.. Along with her obituary came the news that another living woman is now 126 years old, setting a new world record for advanced age.
So What Do We Know?
    We know that in virtually every organism tested so far, certain types of continued stress will cause the organism to switch from a growth-and-reproduction mode to a repair-and-refurbishment mode. 

"Virtually" refers to the interesting fact that in yeast, roundworms or fruit flies in which the Sir2 (Silent Information Regulator-2) gene is missing , calorie restriction doesn't extend their life spans. "Continued stress" refers to food deprivation, and heat stress in animals, and possibly to other types of chronic, low-level stressors. The above link is to the article, "Unlocking the Secrets of Longevity Genes", coauthored by Drs. David Sinclair (Harvard) and Lenny Guarente (MIT) in the March, 2006, issue of Scientific American.

 If the organism is endowed with extra copies of the Sir2 gene it will live longer, but will also be unaffected by calorie restriction.

This raises two interesting questions that the co-authors of this Scientific American article don't mention in their SciAm article, probably because because there isn't room. There are varying degrees of calorie restriction ranging from 0% up to 60%, with corresponding increases in both average and maximum life spans as calorie resrtriction. One question has to do with how calorie restriction is described. The calorie intake of an organism is given by 1/(1 - calorie intake reduction, in %/100).  If I reduce the calorie intake of an animal by 1/3rd  (33.3%), It will be getting  66.6% or 2/3rds as many calories as a fully fed cousin. If I reduced its calorie intake by 2/3rds (66.7%), it would be getting 33.3% or 1/3rd as many calories as its fully fed cousin.


    Furthermore



    If resveratrol acts as a calorie restriction mimetic, then it might provide a deeper level of calorie restriction than, say, 30% calorie restriction by itself. In that respect, it would work better as a partial reversal of aging. Otherwise, it may simply slow the rate of aging.
    It might hard to titer the killfish dosages (in milligrams per kilogram) to human doses because the killfish live so much faster than we do.
    SciAm paper.
    Announcement about 85-year-old retirements.
    Going over a waterfall.
    Adjustments in the economic system that will limit the number of people in retirement.
    Either way, it could be beneficial.




    I suspect that many people aren't yet aware that it may already be possible to, in a sense, subtract 15 or more years from their internal physiological ages, and just possibly, although we may not be certain for decades, add 15-or-more healthy years to their life spans.. In my view, this is a stunning development that might well be one of the most important discoveries of the 21st century. What's most significant about it is that, once the general public learns that something akin to partial rejuvenation is already here, research into the retardation and reversal of aging may go mainstream, like personal computing in 1977.
    This is still very much "bleeding-edge" research, and I'm not suggesting that you rush out and begin practicing these new techniques just yet. However, there are steps you can take at no extra cost, using foodstuffs available at the grocery store, to possibly improve your health and to participate in some experiments aimed at life extension.
    The starting point for these developments is calorie restriction. 
    In 1935,  Cornell University's Professor Clive McKay serendipitously discovered that underfeeding rats extends their life spans by 40%. Since then, more than a thousand studies involving more than 200 animal models have confirmed that underfeeding animals extends their life spans by as much as 60% (for 60% calorie restriction)
("The Longevity Diet", Marlowe Publishing Company, Avalon Publishing Group, N. Y., C., 2005, pg.4). However, several questions were raised about whether, and how well, calorie restriction would work in humans. The calorie-restricted animals were calorie restricted from weaning, and they were late to sexually mature and were stunted as adults. This hasn't been deemed practical,  or ethically acceptable for humans. 
So what happens hhen you calorie-restrict animals later in life?
    The first attempts at placing rats on calorie restricted animals later in life resulted in shortening their lives, but later experiments indicated that if calorie restriction takes place more gradually, it extends the lives of even middle-aged animals.
Is the number of years added to an animal's life proportional to how early their calorie restriction starts?
    This is very important question that Also, it was felt that the number of years added would be proportional to how young calorie-restriction was begun. But in the past few years, two studies have suggested that calorie restriction may be of major benefit even late in life. 
Drs. Dr. Stephen Spindler, Dr. Joseph Dhahbi, and Ms. Patricia Mote show that calorie restriction seems to work even at the latest of advanced ages.
   
In 2001, Dr. Stephen Spindler, Dr. Joseph Dhahbi, Patricia Mote,[http://www.lef.org/magazine/mag2001/dec2001_cover_spindler_01.html] and their co-workers at the University of California – Riverside, put 34-month-old mice that had been 10% caloric-restricted all their lives on a 30% calorie-restricted diet for two weeks, and then on a 50% calorie-restricted diet for two more weeks. At 34 months, these inherently long-lived and 10% caloric-restricted mice were equivalent to extremely old humans… perhaps 95 years of age, or more. How did Dr. Spindler find a large cohort of "95-year-old" mice? 
(1)  These mice were 10% calorie restricted calorie restricted from the time they were weaned to keep them from gorging on mouse chow, and 10% calorie-restricted animals already live 10%-15% longer than fully fed animals. and
(2)  these little-old-lady mice hadn't been allowed to smoke, drink, or drive their Harleys the wrong way down one-way streets.
    At 35 months, the mice were “sacrificed”, and their livers were subjected to a gene-chip analysis looking for age-related changes. Simultaneously, a control group of mice that had been 50% calorie-restricted throughout their 35-month-old lives were also sacrificed, were subjected to gene-chip analysis, and the results compared to the gene-chip results of the 35-month-old mice. To Dr. Spindler’s amazement, the liver genes of the recently-calorie-restricted (35-month-old) mice showed about 70% of the anti-aging effects exhibited by the liver genes of the mice that had been calorie-restricted from infancy.  In other words, the liver cells of these old, old mice had effectively been partially rejuvenated.
    This is a stunning development because it suggests that a partial reversal of aging occurred even in exceedingly old mice.
    Now I know what you're going to ask:  how much longer would these little-old-lady mice have lived if they hadn't been sacrificed at 35 months? For that particular group of mice, we'll never know, but that is a 64-billion-dollar question.: 
    One very interesting and important fact that has emerged from gene chip studies of aging is that out of the 25,000-or-so human genes, only about 2% seem to affect life span. This has considerably narrowed the search for anti-aging genes. Also, it provides a basis for assessing the effectiveness various anti-aging protocols, and is being employed in that capacity.

    Spindler, Dhahbi, Mote, and colleagues also performed gene chip studies on five diabetes drugs (see below) and found that one of them, metformin, induced gene chip modifications that were quite close to those of calorie restriction. 
image Metformin is one of a class of biguanidine drugs derived from the French lilac (goat's rue), which was used for several centuries as a treatment for diabetes mellitus.  It was preceded by two precursors, buformin and phenformin, that caused several deaths through lactic acidosis (up to 60 cases per million), These drugs are contraindicated in cases of hepatic or renal compromise, and of congestive heart failure. Side effects include diarrhea (about 50% of patients) and nausea/vomiting (about 25% of patients) which generally resolve after start and dosage increase. Metformin http://www.healthsquare.com/newrx/GLU1188.HTM is safer than buformin and phenformin, but still. I should think, needs to be taken only under the supervision of a physician.  

    Metformin was approved in France in 1979 and in the U. S. in 1994. The effective dosage range is fairly narrow, ranging between 1,550 and 2,500 mg. a day. (Dosages of 3,000 mg. a day are now being prescribed to treat the more refractory cases of diabetes, although this increases the danger of lactic acidosis. Lactic acidosis is a build-up of lactic acid in the bloodstream when the kidneys can't remove lactic acid fast enough, it and can be fatal.)
    Metformin is one of a class of "CR-mimetics" that seem to trigger the calorie restriction response.
    A 1970's Russian test of phenformin on the  lifespans of female C3H/Sn mice found a life span increase of 23%. Another "quick and dirty" study of the life spans of mice fed metformin was conducted by George Roth, Ph. D. at the National Institutes on Aging, and reported a life span extension of 20%.  (I don't know whether these were average life spans or maximum life spans.) A  more-rigorous study of the effect of metformin on murine life spans was begun by the Life Extension Foundation in early 2004, and is expected to be completed around September, 2007.
     What's interesting about metformin is that it gives some indication of what a CR mimetic--a pill that can induce the effects of calorie restriction without the calorie restriction--can and can't do. Clearly, metformin is no fountain of youth. Type II diabetics (such as my brother-in-law) who take it are typically helped by it, but it doesn't permanently cure them of Type II diabetes.
    Metformin raises several interesting questions in my mind.
    First of all, if metformin is truly a CR-mimetic, then it should induce the same changes we see with calorie restriction--significant elevation of HDL, lowering of total cholesterol, and dramatic lowering of fasting insulin levels in non-diabetic individuals. Does it? Does it produce a profile that matches that of caloric restriction? What's the dose-response relationship?
    In a discussion of metformin's efficacy at lipid control, I've read that at a full dose of 2,500 mg. of metformin a day, improvements in blood lipids are only about ¼ what they are with CR. This is disappointing, but metformin isn't the most promising CR mimetic. That honor goes to resveratrol (discussed below). However, it helps explain why the age-reversal effects of metformin weren't immediately obvious.
    Second, there are varying levels of CR (calorie restriction), with corresponding levels of life extension, and presumably, of gene-chip-detectable genetic modulation. If you combine metformin with CR, will it deepen the level of CR? That would be almost as good as discovering a new aging-reversal mechanism. Most of us can't, or aren't willing to push CR to the maximum. Could we achieve a deeper level of CR through a limited level of CR coupled with augmentation with a CR-mimetic?
    Metformin raises a troubling question. Although aging is the principal risk factor for innumerable diseases, the Federal Drug Administration doesn't recognize aging as a disease. . Consequently, no drugs can be approved to slow, stop or reverse aging.   This means that a drug like metformin can only be officially prescribed to treat frank diabetes. Metformin can't be used to prevent diabetes; only to cure it once it's taken hold. This same situation will hold true for any other anti-aging drugs. Also, it will take a decade or two, and up to a billion dollars to get approval for any anti-aging drug, and then it won't be available except for the prescribed treatment of some other condition.
    Metformin raises another interesting possibility:  are there other drugs that partially reverse the 500-or-so genes that change with aging? For example, how about statins? Statins are broad=spectrum drugs that do far more than just lower cholesterol. The UK is jokingly suggesting that they be added to drinking water, like fluorides. It is also claimed that statins may be available without a prescription within five years. Statins don't raise HDL as much as CR. Perhaps they affect non-overlapping genes. 

Dr. Spindler, et al, Show That Mice That Aren't Put on 54% Calorie Restricted Until the Human Equivalent of 55 Years of Age, Live, on Average, About 15 Years Longer Than 10% Calorie Restricted Mice (That Already Live, Perhaps, the Human Equivalent of 10 Years Longer Than Fully-Fed Mice)
    In their next study*, Dr. Spindler, Dr. Dhahbi, Ms. Mote, et al [
http://www.lef.org/magazine/mag2003/2003_preprint_bio_01.html], over a period of two months (equivalent to about 5½ years in humans), switched a cohort of long-lived 19-month-old mice “at the beginning of old age" (beginning at the human equivalent of about 55) from a 10% caloric-restricted diet to a 54%-calorie-restricted diet (from the age of 60 onward), and then followed them throughout the rest of their lives. (Note that the control group of mice were 10% caloric-restricted.)
    Once on the calorie-restricted diet for two months, the mortality rate for the calorie-restricted mice dropped to about one-third what it was for the control group and about one-fourth 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 the 10% caloric-restricted mice. The longest-lived 10% of these 54%=calorie-restricted mice lived, perhaps, 15 to 20 years longer (in human terms) than they would if they had been fully fed all their lives.
    On his website, Dr. Spindler makes these seminal observations,
    "CR has been viewed as less effective in older animals and as acting incrementally to slow or prevent age-related changes in gene expression. However, we found that mice who begin CR in late middle-age reap its benefits almost immediately. Similar results have also been reported in fruit flies. In our studies, when CR was begun late in life, lifespan was still extended by about six months and CR produced a delay in deaths due to cancer, perhaps by decreasing the rate of tumor growth. Mice put on this diet late in life developed the same patterns of liver gene expression as those who began CR in their youth. Also, when the mice were taken off CR, they returned to their previous patterns of gene expression rapidly. Because liver cancer is the most common cause of death in these mice, the results suggest a cause and effect relationship between dietary calories, the rate of aging, and liver gene expression patterns. No previous study has tied these together so closely in a mammal." 
Dr. Spindler's Experiment (and Others Like It) Tend to Rule Out a Simple "Wear and "Tear" Model of Aging
    These experiments and others like them send an important message about the what's going on with calorie restriction. It's intuitive to think that how long you live depends upon how fast you burn calories... the "candle of life" model of aging (also known as Rübner's hypothesis). This would be like an automobile that ages primarily in proportion to its mileage than in proportion to its calendar age. But if that were the case, then there wouldn't be any reversal of age-related biomarkers when an organism goes on calorie restriction late in life. The organism would age slower for the rest of its life span, but there wouldn't be any improvements in its physical state, or any decrease in the mortality rate. The mortality curve would simply fall off much slower for a few months and then resume its rate of decline. Also, the degree of life extension should be inversely proportional to the rate at which it burned calories. If it burned calories at half the normal rate, it should live twice as long. If it burned calories at 40% of the normal rate (60% calorie restriction), it  should live 1/0.4 = two-and-a-half times as long. But it doesn't work that way. Candles and cars aren't self-replicating, self-repairing devices.
    To quote Dr. Spindler,
   
"The results go against prevailing theories that say slow, incremental changes in gene expression and metabolism are the major cause of aging. They also indicate that many of the important effects of caloric restriction on health begin very rapidly after the onset of the diet. The key genomic effects of CR appear to be rapid, readily reversible, and do not seem to result from the long-term accrual of irreversible molecular damage. Drug therapies that induce the same patterns of gene activity seem likely to produce the same age-retarding effects."
    One important fact to note about calorie restriction is that it doesn't stretch the survival curve. It shifts the survival curve to the right. This means that you stay young longer... that is, calorie restriction increases your "youth span".
    Dr. Spindler observes that 
That's great news for mice, but what does it mean for the rest of us? 
   
It was argued that humans are already an unusually long-lived species, and that restricting calorie intake among humans from weaning would result at best in adding a few years to human lives. It was argued that even if calorie restriction added to life spans the way they do in animal models, it would have to be started at the end of puberty or at least before age 40 to be effective.
Washington University Researchers Show That the Same Partial Reversal of Some Age-Related Biomarkers Occurs in Humans Who Go on Calorie Restriction Later in Life 
    The next important milestone was passed in April,2004, when
a research team at Washington University[1] published in the Proceedings of the National Academy of Sciences[2], the results[3]   of the first study of calorie restricted "longevinauts"[4]  ever conducted[5], 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. This structural change may be the most striking sign of rejuvenation.)
      In a BBC article[6] 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 if . They had been calorie restricted for periods of time ranging from 3 to 15 years, with an average calorie-restricted period of 6 years.
    In the Table below, “Subjects Pre-CR” refers to the blood lipid measurements registered by the 18 volunteers before they began caloric-restriction.

Table 1:  Serial Measurements of Risk Factors for Atherosclerosis in CR Individuals

Parameter

Controls
(Non-CR)

Subjects
Pre-CR

1-Year on CR

Present
Time

%
  Change

Body Mass Index (BMI),kg/m2

25.5

24.5 
(21.9 - 27.1)

20.9
(18.5 - 23.3)

19.5
(17.4 - 21.6)

-20.4 %

Total Cholesterol, mg/dl

205  
(165 - 245)

194  
(149 - 239)

161
(130 - 192)

157 
(129 - 195)

-19.1 %

LDL-C, mg/dl

127
(92 - 162)

122
(86  - 158)

89
(65 - 113)

86
(69 - 103)

-29.5 %

HDL-C, mg/dl

4
(37 - 59)

43
(35 - 49)

58
(45 - 61)

65 
(41 - 89)

+54.7 %

Total Cholesterol/HDL-C Ratio

4.5 
(3.2 - 5.8)

4.1
(3.1 - 5.1)

2.8
(2.3 - 3.3)

2.5
(2.1 - 2.9)

-39.0%

Triglycerides, mg/dl

147
 (58 - 236)

149 
(63 - 236)

112 ± 12  
(100 - 124)

97 ± 8
(89 - 105)

-34.9 %

Systolic Blood Pressure, mm. Hg

129
(116 - 142)

132 
(117 - 147)

112
(100 = 124)

97
(59 - 105)

- 26.5 %

Diastolic Blood Pressure mm. Hg

95
(87 - 103) -

80 
(69 - 91)

69
(62 - 76)

59
(54 - 64)

-26.3 %

    In Table 1 above, the average values for the group of 18 calorie-restricted subjects is shown in maroon. The numbers in parentheses below the average values give the range of values within which the parameters of  2/3rds, or 12 of the 18 volunteers would fall.

Look At What's Happening to Their HDL!
    What seems to me to be striking in Table 1 is the 54.7% rise in the HDL (high-density lipoprotein) value for the group. Statin drugs will lower levels of LDL, but I'm not aware of any medications that will, on average, raise HDL levels by 55%. A rise in HDL may be a valuable biomarker in assessing the effectiveness of CR mimetics.
Look What's Happening to Their Carotid Arteries!
    Another striking change is that of the average 40%-lower thickness of the intima of the experimental subjects'  carotid arteries compared with the average intima thickness for the controls. At the Third Annual Calorie Restriction Society Conference in 2004, one of the co-authors of the April, 2004, Washington University study, Dr. Luigi Fontana, showed a side-by side viewgraph of an ultrasound study of a carotid artery of a 77-year-old runner compared with one of the carotid arteries of the 82-year-old participant in the Washington University study. The carotid artery of the 77-year-old runner exhibited substantial plaque deposits, whereas that of the 82-year-old calorie-restriction practitioner showed none. This suggests a structural change that occurred over an extended period of time rather than a quickly reversible shift in bloodwork numbers. It also seems to me to be consistent with the hypothesis that once the ratio of total cholesterol to HDL approaches 2.5, plaque may be removed from the arteries. In the 58 years that the Framingham Heart Study has followed approximately 5,000 residents of Framningham, Massachusetts, and then their children and now their grandchildren, there has purportedly not been a single heart attack among study participants with total cholesterol to high-density cholesterol ratios of 2.5 or lower.
Look at What's Happening to Their Fasting Insulin Levels!
    A third striking change is that of the average fasting insulin level, which dropped by a factor of more than 3.5 between the initiation of calorie restriction and the time of the study. This would seem to augur well for the avoidance of Type II diabetes.
Are their Improvements Proportional to Their Levels of CR?
    The various cardiovascular values at the "present time" (April, 2004, when these results were reported) are better than they were when the 18 volunteers were one year into their calorie restriction programs. Was that because these volunteers had been on calorie restriction longer by 2004 than they were at one year into their programs, or is it because, judging by their body mass indices, they had lower BMI in 2004 than they did at one year (suggesting a lower calorie intake in 2004 than at the one-year milestone)?

Biomarker BMI TC LDL HDL TC/HDL TG SYS DIAS
% Improvement 72% 89% 92% 77% 81% 57% 57% 52%

  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

The Washington University study demonstrates the same effects in humans as the University of California-Riverside showed in mice: calorie restriction begun later in life not only slows subsequent aging but in a limited sense, actually reverses it by 12-15 years. In fact, it may not slow subsequent aging, but simply "reset the clock", after which aging proceeds at its pre-CR rate. Or the anti-aging effect may be a combination of partial age reversal and slower aging following the limited age reversal. We just don't know yet. 

With 20/20 hindsight, this seems to me to be inherent in Dr. Roy Walford's book, "Beyond the 120-Year Diet" (pg. 44)[7]. 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.
    They also experienced major improvements in health-related indices (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



    This is stunning news. The logical assumption about CR prior to University of California-Riverside and Washington University studies would have been that although CR might slow the rate of aging in the future, there would be no    
    One of the opportunities that the University of California-Riverside and the Washington University studies offer is the possibility of rapidly screening aging reversal agents in humans. 


How Old Is the Oldest Person on Calorie Restriction?

 Insofar as I'm aware, the oldest CR practitioner is also the one who's been practicing CR the longest. He is Ralph Cornell of Massillon, Ohio, who turned 103 in February, 2006. Most of Mr. Cornell's relatives lived into their nineties. Mr. Cornell began calorie restriction in 1953, perhaps before the term "calorie restriction" had been invented. Mr. Cornell sits in his favorite chair, reviewing his papers and records.. Mr. Cornell consumes about 1,200 calories a day, and is 5' 10½" tall. He now receives assistance from his caregiver, Doris Kinnerson, and his grandson, Scott. Mr. Cornell has been a widower for 35  years (since he was 68). He has been a realtor since 1943, adding insurance to his portfolio in 1953. He continued to drive his car to work every day until two years ago, when he broke his hip on his front steps at the age of 101 (because of osteoporosis?).  It appears from the photo that Mr. Cornell isn't the wizened figure we might envision for the very old. Although Mr. Cornell hasn't yet challenged Jeanne Calment's record of 122, he might so far have lived nine or ten years beyond his relatives.

 http://www.amazon.com/exec/obidos/tg/detail/-/1568581572/qid=1085767846/sr=1-1/ref=sr_1_1/104-4365426-4022312?v=glance&s=books    

    Note that I'm not talking about such maneuvers as exercise or  human growth hormones. These strategies may improve your quality of life, but animal studies haven
't shown that such strategies slow the rate of aging..
    I'm aware of four interventions that may extend both the average and maximum life spans for a group of people perhaps fifteen or more years beyond the life spans of a group of matched controls.
    The first and best-documented of these is calorie restriction. 
    





    OK. How sure am I that this is true, and if it's true, why haven't you already heard about it?
    To answer the first question first, this is still in the realm of cutting-edge research, and it's not a clinically proven therapy. There have been more than a thousand life-span studies in animals  confirming the life-extending properties of this phenomenon (calorie restriction). However, although there are several thousand of us availing ourselves of this "rejuvenation" process, there haven't been many studies yet of human subjects.  

Insofar as I'm aware, the longe
What This Might Be Expected to Do for You
    You can probably expect to see your HDL rise by, on average, 55%, and your total cholesterol fall by, on average, 20% to levels such that the ratio of total cholesterol to HDL ranges between 2.1 and 3.1. I have the impression that at these TC (total cholesterol) to HDL (High density lipoprotein) ratios, there is apt to be a regression in atherosclerotic plaque in your arteries.
    You can probably expect to see your systolic blood pressure drop by 35 points and your diastolic B. P. fall by 20 points.
    You can expect to see your fasting glucose drop by 15%-20%.
    You can expect to see your fasting insulin levels fall from, e. g.,  5.1 to 1.4.

    To the best of my knowledge, the individual who has been on calorie restriction the longest is Ralph  of Massilon, Ohio, who began restricting his calorie intake in 1953 at the age of 50. He just celebrated his 103rd birthday.

    This has been known only since 2001, when
Dr. Stephen Spindler, Dr. Joseph Dhahbi, Patricia Mote,[1] and their co-workers at the University of California – Riverside, put 34-month-old lady mice (equivalent to 100+-year-old women*) that had been 10% caloric-restricted all their lives on a 30% calorie-restricted diet for two weeks, and then on a 50% calorie-restricted diet for two more weeks. 

    * - The reason there were any mice left in Dr. Spindler's group of  lady mice at the human equivalent of 100+ years is that even 10% calorie restriction proffers at least a 10%-15% increase in life span over fully fed mice. So, ladies, it helps to keep that slender, girlish figure, after all.

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 50% 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 35-month-old mice. To Dr. Spindler’s amazement, the liver genes of the recently-calorie-restricted (35-month-old) mice showed about 70% of the anti-aging effects exhibited by the liver genes of the mice that had been calorie-restricted since weaningIn other words, the liver cells of these old, old mice had effectively been partially rejuvenated!  
    In their next study*, Dr. Spindler, Dr. Dhahbi, Ms. Mote, et al [2], over a period of two months (equivalent to about 6 years in humans), switched 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, the mortality rate for the 54% calorie-restricted mice dropped to about one-third what it was for the 10% calorie-restricted mice, and on average, the 54% calorie-restricted mice lived the human equivalent of 12 to 15 years longer than the 10% caloric-restricted) mice. The longest-lived tenth of these 54% calorie-restricted mice lived 15 to 18 years longer (in human terms) than they would if they had been fully fed all their lives.
    This is great news for mice, but what does it do for the rest of us?



[1] - http://www.lef.org/magazine/mag2001/dec2001_cover_spindler_01.html

* - also supported by the Life Extension Foundation

[2] - http://www.lef.org/magazine/mag2003/2003_preprint_bio_01.html



[1] - http://www.lef.org/magazine/mag2001/dec2001_cover_spindler_01.html

* - also supported by the Life Extension Foundation

[2] - http://www.lef.org/magazine/mag2003/2003_preprint_bio_01.html

    April, 2004, when Drs. Luigi Fontana, Timothy E. Meyer, Samuel Klein, and John O. Holloszy published a paper, "Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans", in the Proceedings of the National Academy of Sciences, April 27, 2004, vol. 101, no. 17, pp. 6659-6663. (It should be noted that was a small (18 subjects plus 18 matched controls) retrospective pilot study. However, its results agree with those of  various animal studies. Also, subsequent investigations by the above investigators have provided consistent complementary data.) These would be very important results by themselves, but it's their integration into aging research that makes them significant in terms of the possible partial reversal of aging.

    The story begins in 1935 when the chairman of Cornell University's Department of Nutrition, Professor Clive McKay, published the results of his experiment in the underfeeding of laboratory rats. He found that underfeeding his rats by 40%  resulted in extending both their average and maximum lifetimes by about 40%. The lean rats grew up stunted and were late to mature, but they were very healthy and long-lived (equivalent, perhaps, to 120-to-130-year-old humans).
    In the intervening decades, Professor McKay's results have been replicated using animal models ranging from protozoa to primates, and have even found applicable to plants. This repair and refurbishment response appears to have been evolutionarily conserved across all living organisms. Current thinking is that dietary restriction is one of several stressors that include heat shock in animals, and drought and fungus infections in plants, that trigger a switch from growth and reproduction to repair and refurbishment. The organism tries to survive temporarily adverse conditions, so that it can switch back to its growth and reproduction mode again. (Analogous mechanisms might be hibernation or switching to a spore state.) By maintaining calorie restriction throughout an animal's entire lifetime, the animal's body is tricked into maintaining the repair and refurbishment mode from weaning to death.

What Does It Mean to Subtract 15 Years from Your Physiological Age?
    One thing it means is that you can, within a matter of months, lower your chances of cancer, cardiovascular disease, diabetes, Alzheimer's disease, Parkinson's disease and the other degenerative diseases of old age by a factor of 3 or 4. If this is truly a partial rejuvenation, then hopefully, it means that you can add, perhaps, 10-to-15-or-so healthy years to your life span even if you start such a rejuvenation program in your later years.
    Well, the good news is that the most likely way to accomplish this is that  it doesn't cost anything. And the bad news is that the most likely way to accomplish this is that it doesn't take any money. The reason that's bad news is that it means you can't simply go out and buy the,most likely approach--pop an inexpensive pill and l




    What's the dose-response relationship with calorie restriction? How do blood lipids, blood sugar vary with varying degrees of CR?
    Does resveratrol trigger the blood lipid/blood sugar effects of CR? How about aminoguanidine?
    What does resveratrol do to these numbers? Does it deepen the level of CR? Further improve bloodwork levels? Can we amplify the effects of CR using CR mimetics?
    How does this play out with people with varying genetic complements? What about someone who has low levels of HDL? Someone with a familial hyperlipidemia?
    What do Protandim and/or GliSODin do for life spans when fed to Drosophila or C. Elegans? If one or both of these agents extends maximum life span, do they do so by shifting the survival curve to the right or by stretching the curve?