Must We Grow Old?

by Robert N. Seitz

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 & SENS II)

(http://research.mednet.ucla.edu/pmts/sens/sens1.htm)

(http://research.mednet.ucla.edu/pmts/sens/sens2.htm)

(http://research.mednet.ucla.edu/pmts/sens/sen2article.htm)

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

"Is human aging still mysterious enough to be left only to scientists?"

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. 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 spinoff 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?

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. If this fails to materialize, it will be because of a lack of faith in the possibility that this can happen.

I believe that the conquest of aging is feasible, and if it's feasible, it will be accomplished somewhere by someone sometime.

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 few questions:

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. 11¹", 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 "On Living Forever" that he gave in the June, 2000, issue of Ubiquity Magazine.² 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

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).

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-dimethl-thiazolium 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 76, 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 95. 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 90. Aunt Addie was on the pudgy side and died at 100. But Aunt Gertrude died of breast cancer at 76. 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 the Table on page 12. In the first column below are Maximum Life Foundation's daily dosage recommendations of supplements, based upon suggestions from Dr. Lester Packer. Dr. Karlis Ullis, and the Life Extension Foundation. ³ In the second column below are the daily supplements that John Furber is taking.⁴ The third column contains the ingredients in the Life Extension Foundation's Life Extension Mix.⁵

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 to 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.

Dimericine

One product that is wending its way to market is Dimericine ("New cream may repair sun damage to skin".⁶ 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.

Recommended Nutritional Supplements

Ingredient	Max Life	John Furber	Life Ext. Mix
Beta Carotene	5-20 mg.	--	10,000 IU
Vitamin B1	500 mg.	200 mg.	125 mg.
Vitamin B2	100-200 mg.	200 mg.	50 mg.
Vitamin B3	100-200 mg.	300 mg.	187 mg.
Niacinamide	--	140 mg.	(incl. above)
Vitamin B5	500-1,500 mg.	1,000 mg.	600 mg.
Vitamin B6	250 mg.	200 mg.	100 mg.
Vitamin B12	300-500 mg.	200 mg.	600 mcg.
Folic Acid	800 mg.	1,600 mcg. (w/B12)	800 mcg.
Vitamin C	500-1,500 mg.	3,000 mg.	2,605 mg.
Ascorbyl Pal.	--	600 mg.	250 mg.
Citrus Biofl.	--	--	1,300 mg.
Vitamin D3	--	400 IU	400 IU
Vitamin E (mixed)	500 mg.	1,000 IU	400 IU
Calcium	--	1,345 mg.	227 mg.
Chromium	200-400 mcg.	200 mcg.	200 mcg.
Magnesium	--	592 mg.	325 mg.
Selenium	200-400 mcg.	150 mcg.	200 mcg.
Zinc	--	60 mg.	35 mg.
Copper	--	--	1 mg.
Manganese	--	--	5 mg.
Molybdenum	--	--	125 mcg.
Coenzyme Q-10	30-90 mg.	50-100 mg.	--
Lutein	1,000 mg.	--	15 mg.
Lycopene	--	--	3 mg.
Carnosine	--	100 mg.	--
N-Acetyl-i-Cy.	--	1,000 mg.	600 mg.
L-Lysine HCl	--	900 mg.	500 mg.
Methionine	--	120 mg.	--
L-Taurine	--	--	500 mg.
L-Phenylalan.	--	325 mg.	--
Phosphatidych.	--	--	150 mg.

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".

Recommended Nutritional Supplements (continued)

Ingredient	Max Life	John Furber	Life Ext. Mix
Lycopene	45 mg.	--	--
Diaurylthiodip.	--	--	150 mg.
Thiodipro. Acid	--	--	25 mg.
Trimethylglyc.	--	--	100 mg.
Grape seed	50-100 mg.	--	50 mg.
Ginko	120 mg.	240 mg.	--
Green Tea	300-1,200 mg.	1 cup	--
Black tea	--	1 cup	--
Curcumin	900-1,800 mg.	--	--
Glutathione	300-400 mg.	--	--
Biotin	--	400 mcg.	--
BHT	--	500 mg.	--
Breaker 45C	--	100 mg.	--
Alpha-Lipoic Ac.	200-400 mg.	500 mg.	--
Acetyl-l-Carnitine	100-2,000 mg.	415 mg.	--
Choline	--	1,400 mg.	117.5 mg.
Inositol	--	400 mg.	250 mg.
DMEA Bitartrate	--	200 mg.	--
PABA	--	200 mg.	200 mg.
Ibuprofen	--	50 mg.	--
Melatonin	500 mcg.	--	--
Bilberry	100-200 mg.	--	30 mg.
Silymarin	300-600 mg.	--	--
Flax Oil	--	2-4 tbspns.	--
Saw Palmentto Ex.	--	160 mg.	--
Blueberries	--	1/2 cup	--
Strawberries	--	1/2 cup	--
Ginger Root Extr.	--	--	200 mg.
Acerola Juice Ext.	--	--	300 mg.
Alpha-Carotene	--	--	1,000 mg.
Broccoli Complex	--	--	500 mg.
Labiatae Extract	--	--	300 mg.
Rasberry Lf. Extr.	--	--	130 mg.

Footnotes

1 http://puma.protein.bio.msu.su/biokhimiya/contents/v62/full/62111380.htm

2 http://www.megafoundation.org/Ubiquity/West.html

3 http://www.maximumlife.org

4 http://members.aol.com/johnfurber/supplements.html

5 http://www.lef.org/prod_desc/lifemixb.htm

6 http://archives.seattletimes.nwsource.com/cgi-bin/texis/web/vortex/display?slug= skin07&date=20010807&query=Dimericine