Antonio Zamora - Age 66

Once a year, it is good to have a physical check up.  The purpose of the check up is to determine if something is not quite right, and if so, to take steps to correct it.  The most common thing that people find out from a yearly checkup is that their weight has increased.

Gaining a few pounds each year may not seem like a big deal, but over time it can lead to obesity.  An increased amount of fat tissue starts releasing hormones that change the metabolism, and obesity is associated with high blood pressure, diabetes, and cardiovascular diseases.

Over the last year I gained two pounds.  Two pounds may sound trivial, but an increase of two pounds per year over 10 years would be 20 pounds.  By reducing my food by 100 Calories per day, I should be able to lose those two pounds in about two months while maintaining my current level of activity.  Life is full of choices.  Should I give up my daily slice of home-made bread with raw honey or the dark chocolate square?  Maybe I will just cut my portions in half.

We always have to sacrifice for what we want.  In the past, I have been overweight, but I feel healthier when I am lean.  I have to seek the right balance between asceticism and hedonism.  In any case, by next year I expect to be at my normal weight.  That’s my Thanksgiving Resolution.

Dr. Leonard Guarente

Today, I attended a lecture at the National Institues of Health by Dr. Leonard Guarente of MIT.  Dr. Guarente has dedicated his career to the study of the molecular mechanisms that affect life span and the development of the diseases associated with aging.  One of his particular interests is the study of mammalian SIRT genes that are involved in changes in stress resistance and metabolism known to be associated with Calorie Restriction (CR). The CR diet not only extends life span in rodents, but also protects against many diseases of aging, including diabetes, cardiovascular disease, neurodegenerative disease, cancer and osteoporosis.

Dr. Guarente described recent findings in his laboratory regarding SIRT1 function in specific mammalian tissues and in specific disease models.  Dr. Guarente’s lab has recently shown that genetic interventions that enhance the activity of the mammalian sirtuin SIRT1 can mitigate major diseases of aging in mice, such as neurodegenerative diseases and cancer.  Increased expression of the SIRT1 gene in experimental animals was able to decrease cancer, decrease the formation of beta amyloid plaque in the brain, and decrease osteoporosis, but overexpression of the gene was fatal.  It seems that there is an optimum amount of gene expression which promotes health, and that too much is actually worse.

Dr. Guarente posed with me for this photograph.  When I told him that I was a member of the Calorie Restriction Society, he said: “You don’t look too thin.”  I answered that I was not an extreme dieter, and that I only restricted about 10 percent.

 
Hairy and handsome at 21 vs. bald and gray at 65

I recently got an enthusiastic letter from a visitor to my web site who had read the pages about Calorie Restriction (CR) to slow down aging.  He had some questions about resveratrol and other nutritional supplements.  He also had these other things to say:

Do you really believe that the first person to live to 1000 years could be in their 60’s today? (could it be you?)

I’m 22 and am pretty interested in anti-aging. I’d like to stay 22 for the rest of my life. I think with the help you give on your website and maybe even high doses of resveratrol within the next few years. I could stay young long enough to “cure” and maybe even reverse aging.

I believe there’s so much to live for. Technological singularity, colonizing the moon, terraforming Mars, warping space and traveling light years within hours or minutes. We could occupy the Gliese’s and beyond. Maybe map the whole universe! Isn’t all of this worth trying to live to see?

First of all, I am not in favor of taking large doses of anything.  I believe that evolution has fine-tuned the chemical processes in our body and that we can easily upset the balance that gives us life and consciousness.  Also, although I am enthusiastic about technological progress, I am very disappointed about how we are treating the Earth and I think that this will eventually reduce the chance of human survival.  I believe that our way of life will be significantly altered and all the societies on Earth will see dramatic changes due to global warming in 50 or 100 years.  The sea level will rise, and an exodus of people from the coastal areas will begin.  There will be scarcities, homelessness, and human tragedies in a scale that will dwarf what happened in New Orleans in the aftermath of hurricane Katrina. Some nations will completely disappear under water.  Half of Florida will be submerged.  The buildings in Miami will serve as reefs for tropical fish.  In order to live to the age of 1000 years, we would first need to survive the man-made catastrophes that await us as a result of pollution, overfishing, and deforestation.

Last June, I wrote about Aubrey de Gray who is very optimistic about life extension and thinks of aging as a disease that can be overcome using Strategies for Engineered Negligible Senescence (SENS).  These are some of his ideas about aging:

Biological aging is a progressive, degenerative process of decay, in which the healthy cellular and molecular order laid down in our youth slowly falls apart in the face of accumulating aging damage to its functional structures. This damage is a series of unintended biochemical side-effects of normal metabolism. As more and more of our cellular and molecular structures suffer this damage, functionality is lost, and health, resilience, and vitality are slowly taken away from us, leading to increasing age-related pathology.

This is Aubrey de Grey’s Engineering Solution to Biological Aging:

Instead of interfering with the metabolic processes that ongoingly cause aging damage (the “gerontological” approach) or fighting a losing battle to keep badly damaged bodies from falling apart altogether (the “geriatric,” conventional medical approach), the “engineering” strategy is based on the direct repair, replacement, or rendering harmless of the damaged structures themselves. In this approach, metabolism still causes ongoing damage, but the total burden of such damage is repaired well enough to prevent eventual pathology indefinitely.

As I look at myself in the mirror and I compare myself to my old photographs, I can see that my first signs of aging started at 25.  Should a person start preventive senescence engineering at age 25?  If not, how do you get back the hair that you have lost?  Another sign of aging is when your hair starts getting gray.  The body stops producing hair pigment.  This means that something in your body has stopped working.  I am not very optimistic about SENS, but if as a first step these scientists come up with a way of preventing baldness and gray hairs, then I will believe that the “engineering” strategy has further potential.  Until then, I will remain highly skeptical.

Amyloid plaques consist of protein strands misfolded
as beta-pleated sheets through hydrogen bonding

Alzheimer’s disease affects approximately 4.5 million Americans, according to The U.S. National Institutes of Health.  About 5 percent of people ages 65 to 74 and almost half of those ages 85 suffer the disease.  There is no cure for Alzheimer’s. People with the disease experience memory loss, difficulty remembering recent events or the names of familiar people or things.   This disease does not result from normal aging.

Autopsies of people suffering from Alzheimer’s have shown a substantial number of amyloid plaques in their brains.  Amyloids are insoluble clumps of fibrous proteins that have misfolded into beta sheet structures.  Amyloids may also accumulate in other organs and cause amyloidosis which is determined by microscopic histological examination and is characteristic of several different diseases such as inclusion body myositis, a muscle disease, and cerebral amyloid angiopathy.

The increase of Alzheimer’s disease and the increase of obesity in the last 20 years, have caused scientists to explore the idea that specific diets may be beneficial or harmful for brain function.  Indeed, it has been proven that obesity-related leptin levels contribute to the formation of beta amyloid plaques[1,2], and that caloric restriction prevents age-related neuronal damage.[3,4]

If you are overweight, now is the time to get back in shape.  Don’t wait until your body has been damaged beyond repair.  You should exercise regularly and adopt a nutritious, low-calorie diet to maintain your ideal body weight.  You will be a little bit hungry, but you will be healthier.

[1] Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N., Obesity-related leptin regulates Alzheimer’s Abeta. FASEB J. 2004 Dec;18(15):1870-8. PMID: 15576490

[2] Jefferson Scientists Discover Mechanism Tying Obesity to Alzheimer’s Disease

[3] Gillette-Guyonnet S, Vellas B., Caloric restriction and brain function, Curr Opin Clin Nutr Metab Care. 2008 Nov;11(6):686-92. PMID: 18827571

[4] Qin W, Yang T, et al, Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction, J Biol Chem. 2006 Aug 4;281(31):21745-54. Epub 2006 Jun 2. PMID: 16751189

Ipomoea batatas cv. Ayamurasaki

The Japanese island of Okinawa is famous for the longevity of its inhabitants.  One of their traditional foods is a native sweet potato with a deep violet center.  The color of the Okinawan sweet potatoes is due to anthocyanins which act as antioxidants in the body and are supposed to have a multitude of health benefits.  These sweet potatoes are avidly sought by practitioners of Calorie Restriction who are interested in longevity and optimum nutrition.

The Okinawa purple sweet potato was introduced to Hawaii and is occasionally found in the mainland, mainly in Asian markets.  The potatoes take a deep purple color when cooked.  They have a slightly sweet, starchy taste.

Baked Salmon with Okinawa sweet potatoes

The baked salmon illustrated here was prepared by basting with lemon juice, and sprinkling salt, pepper, and fresh dill.  It was baked at 350°F for 20 minutes.  The sweet potatoes were cut into 1-inch cubes and steamed for approximately 15 minutes until they were fork-tender.  Slices of tomato and avocado were used as garnish.

It turns out that mice and men are not that different after all, at least regarding the correspondence between Calorie Restriction (CR) and body weight.  It has been known for a long time that mice or rats allowed to eat only 60% of the control animals, i.e. 40% CR, starting at weaning, grow to be adults which weigh only 50% of the control animals, but they live 30% longer.  The longevity figures have been widely publicized, but the stunting effect of the low calorie diets has not received much attention.  Masoro had some tables documenting the weights of his experimental rats [1], and Mattson [2] provided the following growth chart for mice:

In a recent blog entry about the Effect of Calorie Restriction on Body Size, I provided a graphic illustrating the silhouettes of humans corresponding to the various degrees of calorie restriction to which mice are subjected.  Of course this was just speculation, or so I thought.  However, after tabulating the Mifflin-St Jeor Energy Equations which are used to calculate Basal Metabolic Rate (BMR) for humans,  I found that for proportionally shaped bodies with a Body Mass Index (BMI) of 22, the dependency of weight vs. CR for the humans was identical to the results for the mice.  I had previously discussed this anecdotally in my Calorie Restriction page, but with some additional mathematical analysis, I found that the mouse equations could be derived from the human  Mifflin-St Jeor equations.

I think that there is something intrinsic in the three-dimensional proportions of an organism.  Our genes, or Mother Nature, try to balance the way in which our bodies grow based on the level of nutrients.  A certain amount of muscle is required for every inch of bone growth, and during our growth, we are not overly lanky or overly squat.  If you plant a maple seedling in a big field it will grow to be many feet high, whereas a similar seedling planted in a one-gallon flower pot will grow to be a miniature version of the big tree - a bonsai.  And just like you cannot replant the big tree in the small pot, we cannot cut our calories to levels that cannot support our size.

The correspondence of the mice and human CR equations are discussed here:

Effect of Calorie Restriction on Body Weight

[1] E J Masoro, et al, “Action of food restriction in delaying the aging process”, Proc Natl Acad Sci U S A., 1982 July; 79(13): 4239-4241.
[2] Mattson, et al. “Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake, Proc Natl Acad Sci USA, 2003 May 13; 100(10):6216-6220.

Calorie Restriction (CR) reduces the nutrients available to the body and limits its growth.  We lose weight when the nutrients that we eat are insufficient to meet the requirements of the body.  Conversely, we gain weight when we eat more calories than we burn through our activities.

Exercise stresses the muscles and stimulates them to grow.  With adequate nutrition, the muscles will strengthen and gain mass.  Since the muscles consist mostly of protein, they need additional protein to grow.

Exercise tones the muscles while Calorie Restriction keeps their growth in check.  The combination of dietary restriction and exercise establishes an equilibrium that can be monitored with a bathroom scale.  If your weight increases, you are eating too much.  If your weight decreases, you are not eating enough.

Calorie Restriction with Optimum Nutrition (CRON) is a diet that not only can make you thin, but there is enough scientific evidence that it may also help you to live longer.  The idea behind the CRON diet is to eat slightly less food than you normally would, while meeting 100% of all your nutritional requirements.  A CRON diet requires the use of nutritional software such as CRON-o-Meter to make sure that the food provides complete nutrition.

Here is an example of a one-day menu published by Robert Cavanaugh, a member of the Calorie Restriction Society.  He generally eats twice a day, but has a fruit snack during the day.  The following menu totals 1809 calories with a Protein/Fat/Carbohydrate ratio of 18/27/55.  All nutrients in this menu exceed the RDA except niacin which is 94% RDA.  Fiber content is 40 grams.

Breakfast

Mega Oatmeal recipe:
Ingredients:
1/4 cup (21 g) oatmeal, quick
1/4 cup (20 g) oat bran
2 Tbsp (13 g) sunflower seeds, unsalted,dry roasted
1/3 cup (23 g) milk, dry nonfat
1/2 cup (75 g) blueberry, raw frozen
1 cup skim milk

Instructions:
1. Place first four ingredients in bowl
2. Add 1 cup skim milk, mix
3. Microwave on high 4 to 5 minutes
4. Add frozen blueberries and mix well
5. Add Splenda sweetner if desired

Lunch

One large peach or nectarine during workday

Dinner

Appetizer:

5 Oysters eastern, canned

Main Course:

5 oz. Turkey breast & gravy, frozen
Medium sweet potato
Cup Broccoli spears, frozen
2 large Whole wheat Pita bread brushed with 1 Tbsp Olive oil
8 oz. glass skim milk

1 fruit bowl
1/2 cup seedless grapes
1/2 cup strawberries, sliced
1  cup cantaloupe, cubed

Nuts
2 Brazil nuts
10 Filberts

Dessert:
1 slice Pumpkin Pudding

Pumpkin Pudding recipe:
Pumpkin Pudding is made from canned pumpkin.  Follow the recipe for making the pie filling on the side of the can, but substitute egg whites for whole eggs and substitute Splenda for sugar.  Bake it in a pie dish without any pie crust.  Makes 8 pie slice servings at 70 calories per serving.

Calorie Restriction (CR) is recognized as a scientifically proven dietary intervention to prolong life span. Many people have looked at the graphs in the book by Walford showing increases of 30% in the longevity of mice, and they have decided that they too would like to live to an age of 104 instead of just 80. They learn about Calorie Restriction with Optimum Nutrition (CRON) and they start starving themselves in a controlled way to get rid of the extra fat and keep their glucose levels down.

Unfortunately, many of the promoters of Calorie Restriction diets frequently do not emphasize the stunting effects of the lower calorie diets. Mice started on 40% CR at 9 weeks, when they are weaned, may increase their life span by about 30%, but the lower level of nutrients basically halts the growth of the mice so that at maturity they only reach half of the weight of the control mice[1]. The graphic above illustrates the corresponding relative weights of humans at different levels of caloric restriction assuming that the relationship of weight and CR is linear. If a control human weighed 150 pounds, the 40% CR human would weigh 75 pounds. Using human growth charts, we can estimate that the human control would be approximately 69 inches high, and the 40% CR human would be 57 inches tall.

The more aggressive human calorie restriction practitioners (CRONies) have found that the lower calorie diets decrease their bone structure, causing signs of osteoporosis. Unlike the mice which are started at a young age and can adjust their growth to the level of available nutrients, severe calorie restriction started in adulthood requires the body to decrease in size. Clearly, if the cell metabolism cannot adjust to the lower calorie levels, something in the body must shrink. Studies have shown that the basal metabolic rate can decrease by approximately 16% for metabolically active tissues. Higher degrees of calorie restriction started in adulthood have the potential of causing severe structural damage, and a longer life is not guaranteed.

[1] Mattson, et al. “Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake“, Proc Natl Acad Sci USA, 2003 May 13; 100(10):6216-6220.

Arturo commented:

I feel compelled to make a comment on the graphic. Assuming that one started CR after having grown to one’s full height, say at age 22, wouldn’t the height remain the same? Therefore the growth that CR would stunt would be in the horizontal (X and Y) directions, rather than the vertical (Z) direction in Cartesian coordinates? This would mean that the figures, if they were of adults, would be the same height, but their width smaller?

Arturo is right. The illustrations above are of perfectly proportioned silhouettes which would be produced as a result of normal development.

The decrease of an adult body frame through undernourishment would first be evident in the reduction of muscle tissue because bones are more resistant to modification due to their mineral content. The first stage (acute undernutrition) might produce gaunt bodies like those of the WW II concentration camps or Keys’ Minnesota experiment (right). The second stage (chronic undernutrition) would cause decreased bone mass with related clinical conditions like osteoporosis and its consequences such as kyphosis. The result of severe long-term CR started in adulthood is likely to be a crooked gaunt body, rather than the well proportioned bodies illustrated above.

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