99 replies to this topic

[rshack]

I'm new to this. I'll add a little. There are about 300 different theories of aging. The most well accepted ones are Harman's free radical theory of aging, the mitochondrial theory of aging, telomere shortening (the Hayflick limit), programed gene expression changes causing senescence, and the "garbage theory" of aging, or the accumulation of wastes such as lipofuscin.

I expect most of you have noticed that all these theroies soon look a like after a while. "The rate of living hypothesis" shows how animals with high metabolic rates have a shorter lifespan than animals with low metabolic rates. Shrews live for six months have have very high metabolic rates, and hence high oxidative metabolism and oxidative stress. Some whale species appear to live 200-300 years and have very, very low metabolic rates for mammals. The mitochondira of the short-lived spicies produce very high levles of reative oxygen species (ROS) and these animals have poor antioxidant defense mechanisms. The long-lived species have very efficienct mitochondria that produce relatively fewer ROS. They also have very good antioxidants defense systems. The rate of living hypothesis is essentially another view of the oxygen free radical theory. Long-lived animal species with high metabolic rates have very good antioxidant defense machanisms and mitochondria that make low ROS levels. This also clearly ties into the mitochondrial theory of aging.

Oxidative stress also causes telomeres to shorten more quickly when compared to the same system without the oxidative stress. Telomere shortening in itself also increases oxidant stress and changes gene expression patterns. Last, the pigments that accumulate with aging, like lipofuscin and hemosiderin, are the result of glycosylation and oxidation reactions. Both of these pigments themselves also act as oxidants.

Most of these theories seem to be looking at the same events, with a slightly different view. This is common in science. At one time these was a furious debate over whether the immune system functions on antibodies, or by the activity of immune cells. Eventually it turned out to be both. The two systems turned out to be esentially one coordinated system of cells making antibodies and cytokines to regulate eahc other. I think the theories of aging are the same and most of them are now in the process of merging. Bruce Ames wrote that the rate of living hypothesis has merged with the free radical theory. The other prominant theories will probably merge as well.

That the lifespan of species appears to be detemined by the evolutionary pressure surrounding reproduction should be encouraging. It means that it's probably possible for all mammals, including humans, to live at least several hundred years. Well, please answer me if you have any opinions.

[apocalypse]

Long-lived animal species with high metabolic rates have very good antioxidant defense machanisms and mitochondria that make low ROS levels. This also clearly ties into the mitochondrial theory of aging. -rshack

Elaborating on that a bit more

"There is quite a bit of correlational evidence that longer lived organisms produce fewer free radicals than short-lived organisms," says Brunet. "I became intrigued and began to wonder: Can we attribute the longevity of bats to the free radical theory of aging?" To answer this question, Brunet turned to the same bats and shrews whose metabolic rates she had compared. She isolated mitochondria from the cells of the bats and the shrews and measured their production of free radicals. The short-lived shrews produce twice as many free radicals as the bats. "It seems that the bats have more efficient mitochondria than the shrews, which could explain why they live so much longer despite the similarities in their metabolisms," says Brunet.

With these discoveries, Brunet's research is off to a promising start, and she plans to continue her work during a postdoctoral research appointment at the University of Idaho, where she will work with researcher Steven Austad.

Austad studies longevity in birds, which, like bats, have long lifespans and high metabolic rates. Also like bats, they fly. "It is possible that flight is associated with longevity," says Brunet. "Maybe the energy required for flight requires the most efficient mitochondria and, in turn, decreases the free radical damage that leads to aging."

If that's the case, juvenile bats, which don't yet fly, should produce more free radicals than adult bats. Indeed, Brunet discovered, juveniles produce twice as many free radicals as flying adults.

bats

EDIT:
I wonder if the free radical findings in young bats were also obtained by looking at mitochondrias. IF so, that would mean they weren't born with efficient ones, but became so later on.
EDIT TWO:
Found a paper that further elucidates my comment on herv and related sequences(movable genetic elements)

The recent insertion of a murine intracisternal A-particle (IAP) retrotransposon within one of the introns of a housekeeping gene, the circadian m.nocturnin gene, revealed a singular expression profile, both throughout the daytime and the mouse life span. Measurement of the levels of transcripts from this element by quantitative real-time RT–PCR, in organs of 1–24-month-old mice, disclosed that the inserted element—which is part of a large family of otherwise severely repressed mobile elements—becomes active upon aging, specifically in the liver where the m.nocturnin housekeeping gene is expressed in a circadian manner and induces a circadian expression of the IAP sequence. This age-dependent induction is cell-autonomous, as it persists in hepatocytes in primary culture. We further show, using methylation-sensitive enzymes, a correlation between the life-time kinetics of this process and a liver-specific demethylation of the IAP promoter. These results strongly support a model whereby the progressive demethylation and turning on of the IAP sequence is the sole result of the transient, daily activation—throughout the mouse life span—of its promoter. This phenomenon, which develops on a timescale of months to years in the aging mouse, might reveal a general epigenetic—and stochastic—process, which could account for a large series of events associated with cell and animal aging.

retrotransposon changes in activity

edited

Additional (a little old)link, not sure if it's been posted prior:
DNA Reorganization and Biological Aging

Edited by apocalypse, 22 February 2005 - 04:02 PM.

[cosmicv]

For those against a programmed death theory, how do you explain entities like flies, which only live for a short period of time, but obviously "biological tissue" is capable of much longer functioning?

[gavrilov]

GG) General Comment - Article by Leonid and Natalia Gavrilov - Evolutionary Theories of Aging and Longevity

A really good overview and commentary on the evolution of aging theories: 

http://www.spc.uchic...1/Evolution.htm

Thank you for your kind comments!

Here is a more recent publication on related topic:

Gavrilova, N.S., Gavrilov, L.A. Human longevity and reproduction: An evolutionary perspective. In: Voland, E., Chasiotis, A. & Schiefenhoevel, W. (eds.): Grandmotherhood: The Evolutionary Significance of the Second Half of Female Life. Rutgers University Press. New Brunswick, NJ, USA, 2005, 59-80.

Hope it helps,

[Aegist]

For those against a programmed death theory, how do you explain entities like flies, which only live for a short period of time, but obviously "biological tissue" is capable of much longer functioning?

Evolution...and the lack of selective pressures preventing negative sideaffects and accumulations.

[apocalypse]

For those against a programmed death theory, how do you explain entities like flies, which only live for a short period of time, but obviously "biological tissue" is capable of much longer functioning?

Evolution...and the lack of selective pressures preventing negative sideaffects and accumulations.

I originally thought that, but as I've seen things like altruism, sex, cooperative tendencies and tendencies to punish(often at a cost to the individual/family) unfair behavior, and seeing such spread throughout populations time and again, despite the initial or constant costs/detrimental effects towards an individual and close progeny. It made me realize that if the mathematics allow something to be substantially(or small but noticeably) beneficial for progeny as a whole, it may despite detrimental costs to one or more individuals, slowly spread and like a hook get pulled along ever greater numbers of individuals that compose the species.

[hedleypanama]

ok! First: How elder dies (in macro world)?
well it dies from a arterial thrombotic event (an infarction of any organ: brain, heart, legs, even guts), a cancer or an infectious disease (not mortal on a young one).
Neither of both theories (I prefer to call them hypotheses) alone can explain the problem, because elder persons dies on differents ways... I think both are true because there are NORMALLY cell that must die to the development (like Muller System in males->the become internal genital of women). I have read some research about how diabetics are like aged person. I have a experience to se a young diabetic woman with both arteries blocked, also their appearance seem to be older than their chronological age (it does support, on the top cumulative damage hypothesis).
Theory in science is a word that NEVER MUST BE APPLIED to aging concepts, because now they have a long way to follow before we can understand aging.

[solbanger]

For those against a programmed death theory, how do you explain entities like flies, which only live for a short period of time, but obviously "biological tissue" is capable of much longer functioning?

Evolution...and the lack of selective pressures preventing negative sideaffects and accumulations.

I originally thought that, but as I've seen things like altruism, sex, cooperative tendencies and tendencies to punish(often at a cost to the individual/family) unfair behavior, and seeing such spread throughout populations time and again, despite the initial or constant costs/detrimental effects towards an individual and close progeny. It made me realize that if the mathematics allow something to be substantially(or small but noticeably) beneficial for progeny as a whole, it may despite detrimental costs to one or more individuals, slowly spread and like a hook get pulled along ever greater numbers of individuals that compose the species.

I guess in some species they have what amounts to a programmed death, such as with some species of salmon where after the males compete for females nearly all of them sputter out and die only to shore up at the edge of the river. Some scientists believe that the males suffer a massive burst of free radicals at the climax of their hunt as a penalty for their aggression. But I recall that this event only happens to the males, so the females may be indicative of the species true lifespan in the environment. So I believe programmed death is possible, but tends to be an attribute for animals in specific niches.

Self-destructive behaviors such as altruism and cannibalism seem to make more sense when considering that they serve to maintain the gene rather than the individual. So if you have a group of robins and one of them spots a predator and calls out a distress signal, that one particular robin will expose itself for the sake of his or her cousins, thus allowing the distress signal gene to continue in them. Some genes are designed to operate en mass with other gene carriers. An argument exists whether the human brain itself is a result of our ever-escalating modes of communication, that the brain is designed to work against other brains.

[jamesagreen]

I get the impression that the primary process to watch and correct in human aging is replicative senescence.
The best way to do this is via telomerase activation to rebuild telomeres in senescent cells until telomere t-loops
close, terminating the DNA damage signal responsible for the transition to the senescent phenotype of the cell.
The most inexpensive way to do this at the present time seems to be via taking 5 mg of astragalosides per day in water
from a preparation like GAIA Astragalus Extract in glycerin, in which case we have 1 mg astragalosides per 30
drops, and we need to take 150 drops for 5 mg astragalosides. (There are 180 drops per tablespoon).
However, the rejuvenation rate is about 0.667 years per month to 0.75 years per month, if the telomerase activator
is taken 2 weeks out of 4. I recommend taking all telomerase inhibitors such as garlic, silymarin, melatonin,
green tea, fish oil, and so forth during the next 2 weeks. At this rate, one rejuvenates at a rate of 8 to 9 years
per year of treatment. This is about how fast senescent cells are transitioned to the immortal (youthful) phenotype
of the cell. If this is correct, a 60 year-old specimen can rejuvenation into an effectively 20 year-old one in 5 years.
The rate is glacial, however, like aging itself, so that results are scarcely seen for about 9 months or so. It would be useful to measure
telomere growth during the rejuvenation process with tests run at Repeat Diagnostics ( < $700 per measurement
of lymphocyte and granulocyte telomeres), or perhaps at TA Sciences. This allows one to get a better quantitative handle on the rate of the
rejuvenation process. This sort of treatment scheme should modify maximum human lifespans, allowing mitotic
cells and stem cells to divide many additional times. However, it will also be useful to do the things that modify
average lifespan, such as implementing DNA and cell membrane protection with antioxidants. Cocoa powder in
water, taken chilled at two tablespoons per wine glass full, makes a fine antioxidant, as does alpha lipoic acid,
which is reasonably priced these days. I would suggest acetyl L-carnitine with alpha lipoic acid for mitochondrial
rejuvenation, together with 3 grams of arginine daily with exercise is also useful. The extra arginine works
with exercise to produce Nitric Oxide that lengthens the telomeres of endothelial cells in arteries, deflecting
atherosclerosis. Cocoa also tends to defend against atherosclerosis. A homocysteine blocker using vitamin
B6, B12, and folic acid with perhaps TMG (trimethylglycine), not only reduces the likelihood of atherosclerosis
leading to heart attack and stroke, but also tends to preserve telomere length. Also, the exercise discipline
with extra arginine (tuna, spanish peanuts are good sources) helps with mitochondrial genesis.
Long telomeres in humans are associated with youthful patterns of gene expression, resulting in youthful
dermal fibroblasts that emit collagen and elastin rather than senescent dermal fibroblast collagenase
and stromelysin, which attack the extracellular matrix. Prospects for rejuvenation using off-the-shelf
pharmaceuticals already available are good if the astragalus extract is used to regrow telomeres. Otherwise,
I think we usually observe some mere decelleration of the aging process, instead of a reversal to a more
youthful state.

[AgeVivo]

GG) Aging as combined degradation
I guess I should state my personal opinion that aging is a combination of a few different degradation processes that lead to multiple component failures. It is just a matter of what gets you first. In the oldest old, you see complete system failures, where everything just falls apart.

I'd personnally favor this view too (in the Reliability theory of aging, it is what happens to the High Initial Dammage Load: vital organs slowly accumulate non functioning cells until one vital organ failure: this perfectly matches all features of empirical lifespans), modulo
- the fact that some dammage can take over the body (such cancer)
- the fact that the body has natural ways to clean/slow down the damage loan under some circumstances (such as CR).
However, this does not give us much information on how to fight aging.

telomerase activation to rebuild telomeres in senescent cells (...) 5 mg of astragalosides per day (...) telomerase inhibitors such as garlic, (...) during the next 2 weeks. (...) measure telomere growth (...) Repeat Diagnostics (...) DNA and cell membrane protection with antioxidants (...) Cocoa (...) alpha lipoic acid, (...) acetyl L-carnitine (...) 3 grams of arginine daily with exercise (...) against atherosclerosis (...) A homocysteine blocker using vitamin B6, B12, and folic acid with perhaps TMG

Difficult to know whether you are serious with those knowledgable wishfull thinkings. Isn't telomerase activation pro-cancerigenous? Why mixing it with telomerase inhibition? Is it what you are doing/what someone else is doing? If so, when did it started, and what are the first results of measurements? Otherwise, isn't there a simpler specie (eg mice, pigs) where this might be tested first? Thank you

Edited by AgeVivo, 17 November 2008 - 08:46 PM.