Must We Grow Old?

Biologists are rapidly closing in on the secrets of aging. 
    One group of research gerontologists has set as its publicly announced goal the demonstration of the reversal of aging in a mouse by about 40% by 2012. See:

Strategies for Engineered Negligible Senescence (SENS) I (http://research.mednet.ucla.edu/pmts/sens/sens1.htm)

Strategies for Engineered Negligible Senescence (SENS) II (http://research.mednet.ucla.edu/pmts/sens/sens2.htm)

"Time to Talk SENS: Critqueing the Immutability of Human Aging"

"Is human aging still mysterious enough to be left only to scientists?" (http://research.mednet.ucla.edu/pmts/sens/sen2article.htm)

    These gerontologists are trying to get the word to the world that aging reversal--not just aging retardation-- is imminent, and that the public needs to be aware of it, since there are questions that need to be answered before this technology suddenly looms large.

    Caloric Restriction
    It was demonstrated in 1935 that caloric restriction will slow the rate of aging in rats by an amount roughly proportional to the degree of caloric restriction. Innumerable experiments since that time have shown the same "youth extension" through caloric restriction in every organism with which it's been tried. Several "longevinauts", following the lead of Dr. Roy Walford, are trying this approach to the retardation of aging. In the meantime, a study of caloric restriction in primates is underway at two locations, and preliminary results suggest that the same kinds of effects observed in other mammals are taking place with the primates.
    The Methuselah Gene
    A Harvard spin-off is trying to bring to market a product or products designed around the "Methuselah" gene that confers long lives upon centenarians.
    Will You Live Longer, and Prosper?
    I believe that the conquest of aging is feasible, and if it's feasible, it will be accomplished somewhere by someone sometime.
    The bottom line is that you might want to keep in the back of your head the possibility of a longer life than most of us have planned. How rapidly this happens depends upon how much effort is expended to make it happen. But the public needs to be apprised of the fact that the retardation and/or reversal of aging is possible, and that it's getting ready to happen. (In a sense, it's already happening.)

How Can Babies Be Born Young?
    Have you ever wondered how babies can be born young when the cells that give rise to them may be from 15 to 70 years old? We know of no way to totally rejuvenate either cells or people. Why aren't babies born with an age that's some sort of average of the ages of the cells that created it?
    It's clear that every species must have some way of making brand-spanking-new copies of its kind across countless generations. Deviations (mutations) in the genetic specifications defining the species may occur, but partial aging of new organisms cannot be allowed to accumulate. Otherwise, life on Earth (and we ourselves)  wouldn't be here.
    So what's happening?

Nature Must Know the Secret of Total Rejuvenation
    It's clear that Nature has some means of completely rejuvenating organisms at the time of the reproduction cycle, so that their offspring have their biological clocks reset to zero.
    The contents of the documents may change, but they will always be printed on new paper.
    What's so striking about this is that
(1)  It has to be perfect! If there were any cumulative aging passed on to succeeding generations, they would eventually be created too old to survive.
(2)  This has to be present for every life form on this planet from their first instantiation onward. Otherwise, they wouldn't be here. That means that we're looking for machinery that may be found in the simplest, archeozoic prokaryote to the most modern, complex eukaryote.
    It has to be happening in unicellular life forms, as well as in multicellular organisms that reproduce sexually or parthenogenically.
    To say it again, Nature has been perfectly rejuvenating organisms under our very noses since time immemorial! 
    So how can we learn how to do this?
    One approach might be to examine the simplest organisms.
    I first became cognizant of this reality when I read Advanced Cell Technology's announcement, in April, 2000, that they had successfully cloned eight calves. What seemed striking to me in that press release was the fact that the egg cells were enucleated, and that somatic cells from a very old cow were implanted in them in lieu of spermatozoa. Somehow, the rejuvenation process took place in its customary way, and the calves were born with longer telomeres than calves produced in the conventional way.
    This raises a question or two: 
(1)  Since the nuclei of the egg cells were no longer present, the old and damaged nuclei of the somatic cells from the old cow must somehow have been reconstituted so that they were young again. More specifically, their telomeres were re-established. Another crucial question might be: was genetic damage to these nuclei completely reversed? 
(2)  How did the somatic cells know that they were in egg cells?
(3)  Something in the cytoplasm of the egg cells must have triggered the rejuvenation cycles, since the oöcyte's nuclei was no longer present. 
(4)  The rejuvenation cycles must have occurred rapidly, either in the "fertilized zygotes" prior to mitosis, or in the daughter cells immediately after mitosis. 

This Reconstitution Process Must Occur in Protozoa As Well As In Multicellular Organisms
    This process must also take place in unicellular organisms that reproduce by parthenogenesis. Either they have intrinsic maintenance mechanisms that keep them always in the pink of condition, or reconstitution must occur when they divide. In other words, either cells that reproduce are immortal and perfectly self-repairing, or perfect rejuvenation occurs when the cell reproduces.
    The first possibility, that germ plasm is immortal, was advanced by Weisman in 1891.
    More recently, Leonard Hayflick ("Mortality and Immortality at the Cellular Level", Biochemistry (Moscow), Vol. 62 (1997), No. 11, http://puma.protein.bio.msu.su/biokhimiya/contents/v62/full/62111380.htm) has argued that unicellular organisms are mortal, and that rejuvenation only occurs when there is the periodic exchange or reorganization of genetic material). 
    The importance of this distinction is that if certain cells rejuvenate when they divide, we could look for a sudden cascade of DNA and protein repair enzymes, and other restorative molecules within the cell when it prepares to divide.
     If not, then we have to examine the differences between immortal cells, and cells that don't eliminate aging when they divide.
    Dr. Michael West (CEO of Applied Cell Technology) discusses it in the interview (http://www.megafoundation.org/Ubiquity/West.html ) "On Living Forever" that he gave in the June, 2000, issue of Ubiquity Magazine. So the information is out there. The only question is: why don't you hear more about it? To me, it was a revelation on a par with Hahn and Strassman's splitting of the uranium atom in 1939... a discovery so momentous that governments of that era raced to capitalize upon it. The $$$ involved in total rejuvenation would be mind-boggling, together with momentous implications for society.. My guess is that even if this can occur only in fertilized ova, there are mechanisms--e. g., DNA repair mechanisms--that can probably be pressed into service to rejuvenate adult cells. Of course, neurons and myocytes are post-mitotic, and don't divide, so they might be restored to a virgin state, but I wouldn't expect missing cells to be replaced. That would require some other maneuver... viz., stem cell infusions.

Some Mechanisms of Aging
    Aging is now considered to be almost entirely a byproduct of energy generation in the mitochondria. This is where most free radicals are generated, as carbohydrates, and to a lesser degree, fats and proteins are burned to power the cells.
    Carbohydrates are now considered more dangerous than fats. 

    Telomeres - The DNA Replication Counter
    One of the mechanisms of aging is the "replication counter" embodied in the telomeres. The telomeres are caps on the ends of chromosomes that keep them from fraying. For differentiated, dividing cells, the telomeres shorten each time the cell divides. Eventually, the telomeres become very short, and irregularities in cell division and function begin to occur. Finally, the telomeres vanish, and further cell division is impossible. The maximum number of divisions allowed varies from species to species. In humans, about 80 to 90 divisions are possible in vitro.
    The telomeres can be restored with a ribonucleoprotein called telomerase.Telomerase is missing in most human somatic cells, although it's present in human germ cells and in cancer cells.
    However, telomeres don't normally get short enough in humans to halt cell division. Also, the  post-mitotic (non-dividing) cells found in central nervous tissue and muscle tissue don't divide,  anyway, so any aging that occurs in them must have nothing to do with the shortening of the telomeres (although a loss of effectiveness of supporting tissue could hamper them).
    You wonder why the body can't be flooded with a one-time shot of telomerase to lengthen the telomeres on the ends of the chromosomes. Since cancer cells generate telomerase, there has been concern that administering telomerase might promote cancer. ("All algae are green. Therefore, everything that's green must be algae.") But germ cells and some rapidly-dividing cells of the body, such as hematopoietic cells in the bone marrow, and keratinocytes in the skin, generate telomerase without becoming malignant. Cancer cells already produce their own telomerase, so they shouldn't be affected by an exogenous perfusion of telomerase. Experiments in mice should show what would happen if you tried this, but so far, I haven't found any such experiments.
    Glycation - Damage to Proteins
    Glycation is sometimes called the "browning" reaction because it's like the browning of meat, or the yellowing of paper. Cross-linking of the proteins contributes strongly to cardiovascular disease, kidney disease, arthritis, stiffening of the skin, cataracts, complications of diabetes, and Alzheimer's Disease. Aspirin and carnosine seem to slow the development of Advanced Glycation End products (AGE's). Crosslink breakers similar to vitamin B1 are under development. The furthest along is 3-phenacyl-4,5-dimethlthiazolium chloride, developed by Alteon Pharmaceuticals and showing promise in Phase 2 clinical trials.
    Lipofucsin (Sludge) Build-Up in the Lysosomes (Recycling Plants) of Cells
    Lipofucsin or ceroid is a highly cross-linked product found in the lysosomes or recycling plants of non-dividing cells. This indigestible sludge builds up until it can interfere with the recycling of waste products in the cell, and may even cause leakage of the highly reactive breakdown enzymes from the lysosomes into the surrounding cytoplasm, with harmful results.
    Mutated Mitochondrial DNA
    The mitochondria are the powerhouses of cells, converting sugars into a form that can be used to fuel cells. The mitochondria and the lysosomes are "hot spots" within the cell containing very corrosive molecules. If they don't function properly, they can cause a lot of mischief. 

What's Available for You Right Now for the Possible Retardation of Aging?
    Total rejuvenation is an extreme case of the gradual extension of the life span and of the "youth span" of the average person that has occurred over the past few hundred years. Various forms of additional extension of the average life span are possible, ranging from better health habits, to caloric restriction, to, possibly, some kinds of "prolongevity" interventions.

    Are Our Lifespans Written in Our Genes?
    I don't have a solid answer to that. A search on Google for "identical twins"/lifespan yielded conflicting results. A couple of reports said that 35% of lifespan variability is genetically determined, and 65% is environmentally modulated. On average, twins dates of death are 7 years apart. On the other hand, 60% of all centenarians had at least one close relative who had also been a centenarian. In my own family, there was one uncle who smoked like a furnace and drank like a fish until he was 77, Then his doctor told him he could either quit or die. He chose to quit, and died at 90. He had a younger brother who died in his early 70's of a stroke. Aunt Florence was a health food enthusiast and died at 94. Uncle Glen was still cracking jokes and driving his truck until a few days before he died (of a stroke) at 94. He scoffed at health foods, and loved meat, potatoes, and gravy. There was Aunt Ava, who was very overweight and loved pop tarts. It eventually killed her, at 95. But Aunt Gertrude died at 76, of breast cancer. 
    Of course, there's no way of knowing whether Uncle Glen and Aunt Ava could have lived a few years longer had they taken better care of their health. 
    I think there's something to the genetic model, but I think that environment also plays a role. Alcoholics and high rollers often die in their forties. Lung cancer often hits in the fifties and sixties. And when it comes to these supplements, we're on virgin ground. In animal studies, feeding animals antioxidants elevates the average age of death, but not the maximum life span. However, raising the average life span (if indeed they can do this) would be quite fine. Here. though, some of these supplements might possibly modulate the rate of aging, since they contain more than merely antioxidants.
    Diabetes was a certain death sentence in 1900. Today, many diabetics can control their diabetes with diet alone. In 1900, a family history of hypertension or heart disease was an almost certain sentence of early death. Today, there's a great deal we can do to extend the lifespans of people with such predispositions, even to the point of achieving normal lifespans. 
    What I believe is that better diet and medical interventions may reduce your risks of cancer, cardiovascular disease, Alzheimer's Disease, and Parkinson's Disease. And right now, the name of the game is to hold on while improvements in aging intervention appear. 

    The Guidelines Are Shifting From Low-Fat to Low-Calorie
    Twenty years ago, the dietary emphasis for healthy living was centered around low-fat diets. Low-fat diets are still "in", but the principal cause of aging is now considered to lie in the calories that we consume. Free radicals, primarily involving oxygen, and primarily produced by energy generation in the mitochondria, are considered to be to the drivers of aging. The ingestion of various kinds of antioxidants is a crucial component of early 21st-century aging-mitigation programs.

    Let's see what's out there for you now, and what's in the pipeline for the near future.
    First of all, you can extend your youth span by avoiding activities that are obviously harmful to you. For example, sunlight is devastating to your skin. A tan (not just a sunburn) is a mark of DNA damage to your skin. 
    Second, you can eat foods that may protect you from cancer. Generally, these are foods containing antioxidants, such as brightly colored fruits and vegetables. New foods are being added as time goes by. Two servings of fish a week are suggested, with one of them being one of the fatty thalassic fish containing the omega-3 fatty acids, such as salmon, tuna, mackerel, or whitefish (but not cod). (A British health watch organization has just warned against eating more than one serving of fatty fish a week because of the PCB's, dioxin, and mercury in them.)
    Among the older recommended foods are broccoli, cabbage, spinach, and carrots. Apples, oranges, purple grapes, and recently, strawberries and blueberries have been added to this list. Green tea is being recommended for its beneficial properties. (You can buy the essences of many of these fruits and herbs at Walmart.)
    Third, you can take nutritional supplements that may also, hopefully, afford cancer protection as well as resistance to aging. Here, there are as many expert opinions as there are experts. Three sets of recommendations are presented in Table 1, below.

    In the first column below are Maximum Life Foundation's (http://www.maximumlife.org) daily dosage recommendations of supplements, based upon suggestions from Dr. Lester Packer. Dr. Karlis Ullis, and the Life Extension Foundation.
    In the second column below are the daily supplements that John Furber (http://members.aol.com/johnfurber/supplements.html) is taking.
    The third column contains the ingredients in the Life Extension Foundation's Life Extension Mix (http://www.lef.org/prod_desc/lifemixb.htm). 

    As you can see, there's no universal agreement regarding what supplements one should take.
    One factor to consider is the cost of these "nutritionals". Costs would eat you alive if you tried to buy all of these supplements  individually. For this reason, the "Life Extension Mix" from the Life Extension Foundation sounds promising o me. It's advertised as costing $1.36 a day (plus the annual cost of membership in the Life Extension Foundation). That might sound like a lot, but when you consider the cost of buying even a fraction of this at Walmart (let alone a health boutique), it begins to look like a pretty good deal. I'm not prepared to recommend anything at this time because I don't yet know that much about these choices.
    In any case, if you're going to buy nutritional supplements, and most people do these days, then the three of these supplement lists are probably a better choice than what's available at Walmart. 
    You could probably find all this at your local health food store, but it would cost you an arm and a leg.

Exercise
    Exercise--and this includes strength-building exercise as well as aerobic exercise--is beginning to receive star billing in the war on aging. It is being found to play a far more important role in maintaining health than was realized ten years ago. (One of the ideas that has been publicized for a long time is the fact that aerobic exercise can seemingly take 20 years off the age of your cardiovascular system. Of course, it doesn't really make your cardiovascular system 20 years younger, nor should it replace the mitigation of high cholesterol levels and other risk factors for cardiovascular disease.)

Dimericine
    One product that is wending its way to market is Dimericine ("New cream may repair sun damage to skin", archives.seattletimes.nwsource.com/cgi-bin/texis/web/vortex/display?slug=skin07&date=20010807&query=Dimericine). 

    Dimericine is a cream containing a DNA repair agent harvested from pelagic bacteria and algae, and delivered via a viral transfection agent. Dimericine is in Phase IV FDA testing, and has been shown to reduce the incidence of skin cancers by about one-third, and of actinic keratoses by about two-thirds. The company that developed it, Applied Genetics, Inc.--Dermatics, has licensed cosmetic rights to a company called Elan Pharmaceuticals with the hope of eventually including Dimericine in suntan lotions. (It may prove to be too expensive for that purpose.) In the meantime, two companies are selling a "DNA repair cream" (both are selling the same cream and are making the same claim) that is ostensibly Dimericine, although they don't claim that on the bottle. I'm trying it on my left hand, and on the left side of my face. The results are too early to call just yet. The cream is very expensive, running $45 a bottle plus $10 S&H from Synergy, or £21.99 + £3.50 S&H from Apple Healthcare in the UK.

Other "Dermaceuticals"
    A companion product was discussed on a recent ABC documentary. It would appear that there are now several treatments that will actually reverse aging in skin. Tommie Jean happened to be tuned in to the original TV program when it was shown on ABC night before last. They showed before and after pictures taken in a research study of a stem-cell cream, and pointed out the (visible) changes in women's jaw lines and sagging jowls that were firmed up by their experimental cream. There were also two other approaches described in the article and presented visually in the TV special. I haven't tried them yet, but I may.
    As I understand it, these biological agents partially and "permanently" (for many years) reverse aging in skin. Of course, the next question that crosses your mind is: What would happen if you were to take it internally? I presume that's been attempted with animal models. (I certainly wouldn't want to be the first one to try it.)

Acetyl-l-Carnitine and Alpha-Lipoic Acid
    Dr. Bruce Ames, et al, recently reported in three articles in the Proceedings of the National Academy of Sciences that the simultaneous administration of two naturally occurring food supplements, acetyl-l-carnitine and alpha-lipoic acid, had extended the maximum life spans of laboratory rats by about 50%. Dr. Ames and his colleagues were repeating similar studies performed by other researchers, who obtained similar results. Dr. Ames is known for his Ames Test of Mutagenicity.)
    Carnitine and  lipoic acid  are members of the B-vitamin family found in red meat.

    Tommie and I have been taking acetyl-l-carnitine and alpha-lipoic acid for about six months. Does it make a difference?
    Of course, it's very hard to say. I don't know how we would feel without it. (We've upped our dosage of acetyl-l-carnitine to 500 mg. a day  and of alpha-lipoic acid to 300 mg. a day, since this seems to be the "going dosage".

Cosmetics as a Showcase for Anti-Aging Technology
    If there's one place where I would expect to see anti-aging technology strut its stuff, it would be on milady's face. And "see" is the operant word. With skin, you can see the ravages of Father Time--and their remediations--at a glance. Furthermore, women (and some men) are willing to pay great sums to improve their appearances. Add to that the fact that applying something to a patch of skin is safer than ingesting it, and you have three important ingredients that might drive anti-aging technology.
    Dr. Nicholas' Perricone's, "The Wrinkle Cure"
    Dr. Perricone is an Assistant Professor of Dermatology at the Yale School of Medicine. He has written a book called, "The Wrinkle Cure", available from Amazon.com for $11.(or $5.50 used). He has experimented with "nutritional" supplements in retarding and reversing age-related skin damage. (Most damage, he says, is photolytic.) He includes general health in his appearance-improving strategies. His principal "cosmeceuticals" are ascorbyl palmitate, the tocotrienols, CoQ-10, the alpha-hydroxy acids (lactic and glycolic acids) and the beta-hydroxy acids (salicylic acid... as in wintergreen oil), alpha-lipoic acid, and DMAE (dimethylaminoethanol).
    Dr. Perricone subscribes to the cell membrane hypothesis of aging, and has found that fat-soluble nutrients such as ascorbyl palmitate are effective at minimizing such damage.
    Dr. Perricone also describes two approaches to combating aging that are currently in the pipeline.
    One of these is the discovery of agents that will trap free radicals until antioxidants can reach them. These substances are nitrones, the first of which was phenylbutyl nitrone (PBN, 1990). A family of other nitrones has since been synthesized that show 10 to 20 times the radical-trapping activity of PBN. Their application to the skin will probably come sooner than their whole-body application.
    The other is telomerase. Dr. Perricone believes that telomerase will be on the market in 5 to 10 years, and can be used for skin care much sooner.
    It interested me that Dr. Perricone is, in a way, a gerontologist as well as a dermatologist, because this is what it takes to restore aging skin.

Some Problems that Attend Life Span Extension
    I won't dwell expansively on this now because this will be discussed in a follow-on article in next month's "Gift of Fire" (together with whatever else I learn over the next month about anti-aging technology), but here are a few thoughts in passing:    
    The first problem that comes to everyone's mind when the subject of longer lifespans arises is that of overpopulation. However, after thinking about it, I'm not sure that it's as serious a problem as it at first seemed to me to be.

(1)  Over the past century, average family size has increased from, perhaps, 5 children per family to 2 children per family. This has occurred without any official action... no "Bureau of Population Control", for example.
(2)  U. S. life expectancy has risen from 47 years in 1900 to 78 years in 2000. In other words, we've already weathered a 1.65 increase in average life expectancy. A comparable increase between now and 2100 would see an average life expectancy at birth of 129 years!
(3)  The past thirty years has witnessed a sexual revolution, with sexual relations beginning earlier, more children born out of wedlock, and many unmarried couples living together. One might have expected this to precipitate a population explosion, but it doesn't seem to have happened.

Modern Medicine Extends Lives
    Clearly, any improvements in medicine--in fact, any medical attention at all--has the effect of extending people's lives.   Every time a physician performs an appendectomy or administers antibiotics to cure a life-threatening infection, she is prolonging someone's life in a serious way. It would seem to me that medical intervention in a potentially life-threatening situation would, hopefully, lead to life extension.    

Average Lifespans Will Rise Worldwide As less-Industrialized Nations Catch Up with More- Industrialized Nations
    Population growth rates have been declining for 30 years, and populations are actually declining in some Western nations. (Part of our population growth in the U. S. is a result of immigration.) The U. N. is forecasting a global population peak of 9,000,000,000 by 2070, followed by a gradual decline.

Future Problems May Engender Future Solutions
    We tend to think in terms of the solutions that are evident to us today. However, future technology and/or future  cultural changes may bring forth solutions that many of us wouldn't casually foresee today. In 1952, most people wouldn't have foreseen The Pill, or women working on construction crews.

Lifespan Extension Is a Touchy Subject
    There are some people, including some gerontologists, who are opposed to youth extension.... until they develop cancer or pneumonia. I have yet to hear anyone say, "How wonderful! I've got pneumonia. I won't try for an antibiotic. That way, I can reduce the population by one, and I can get to Heaven sooner." I suppose it happens, but even my most devout church friends pray for recovery rather than death.
    Aging is inextricably intertwined with degenerative diseases, and even somewhat intermeshed with vulnerability to infectious diseases, and that's why I believe we'll opt to do everything in our power to conquer diseases and to heal the sick.
    Forcing people to die of degenerative diseases if a cure for aging is at hand would seem to be, in my opinion, a form of genocide.
    Please stay tuned to this station until next month's exciting episode..