http://sageke.scienc...ate&days=60#330
As I was looking for contact info I came across this hot off the press letter on their bulletin board that seems to be very helpful in setting the stage for interest in the up coming conference. Here is the letter in this area for discussion. There is a link on the above page for making a reply directly to them and it might be helpful to have a parallel discussion here as well.
Making Sense of SENS: Criticisms and Suggestions
10 October 2005
E-mail Ben Best
Too many biogerontologists place too much emphasis on genetics and cell signaling, as if longevity were controlled like puberty and menopause. True enough, an organism can upregulate anti-oxidant enzymes, DNA repair, autophagy and heat shock proteins in response to cell signaling. But this only emphasizes the more fundamental truth about aging: that aging is damage to macromolecules, cells, tissues and organs. Damage, not cell signaling, is the fundamental issue in aging. I believe that Aubrey de Grey is correct in his premise that molecular repair is the only approach that can significant ameliorate the damage known as aging.
My rewording of Aubrey's seven molecular repair strategies is as follows:
(1) Cell loss can be repaired (reversed) just by suitable exercise in the case of muscle, but for other tissues it needs various growth factors to stimulate cell division, or in some cases it needs stem cells.
(2) Senescent cells can be removed by activating the immune system against them. Or they can be destroyed by gene therapy to introduce "suicide genes" that only kill senescent cells.
(3) Protein cross-linking can largely be reversed by drugs that break the links. But for some of the links we may need to develop enzymatic methods.
(4) Extracellular garbage can be eliminated by vaccination that gets immune cells to "eat" the garbage.
(5) For intracellular junk we need to introduce new enzymes, possibly enzymes from soil bacteria, that can degrade the junk that our own natural enzymes cannot degrade.
(6) For mitochondrial mutations the plan is not to repair them but to prevent harm from the mutations by putting suitably modified copies of the mitochondrial genes into the nucleus by gene therapy. The mitochondrial DNA experiences so much mutation damage because most free radicals are generated in the mitochondria. If mitochondrial DNA can be moved into the nucleus it will be better protected from free radicals, and there will be better DNA repair when damage occurs. All mitochondrial proteins would then be imported into the mitochondria.
(7) For cancer (the most lethal consequence of mutations) the strategy is to use gene therapy to delete the genes for telomerase and to eliminate telomerase-independent mechanisms of turning normal cells into "immortal" cancer cells. To compensate for the loss of telomerase in stem cells we would introduce new stem cells every decade or so.
(To read Aubrey's wording see his SENS Overview page.)
(7) is not really about aging. If cancer is to be included in this list then (8), infectious disease, should be included because immunosenescence increases vulnerability to infection as much as it increases vulnerability to cancer. Infection is a major killer of the elderly and biological warfare must be waged against infectious disease much as it must be waged against cancer. (6) & (7) are not repair of damage, so they are not consistent with the presumed SENS program of damage-repair.
For those who are at war with aging, there is an urgency to prioritize these items in terms of impact on the aging process as well as in terms of achievability. Contrary to Aubrey's assertion that understanding the mechanisms of aging is not necessary to SENS, prioritization cannot be done effectively without such understanding. I am among those presumptuous enough to believe that I have some understanding of the mechanisms of aging.
Damage to DNA -- mitochondrial (mtDNA) and nuclear (nDNA) -- seems to be the damage that is most central to aging. Nearly all of the "accelerated aging" diseases involve defective nDNA repair. DNA repair capability correlates with lifespan in mammals [MECHANISMS OF AGING AND DEVELOPMENT; Cortopassi,GA ; 91(3):211-218 (1996)]. For nDNA, defective DNA repair along with associated cell senescence & apoptosis leads more to aging, whereas the DNA damage itself leads more to cancer. For mtDNA damage, the damage becomes most serious when the lysosomes are no longer capable of removing defective mitochondria which are producing high levels of free radicals. Free radicals are the primary cause of the nDNA and mtDNA damage. Defective mitochondria play a central role in accelerated apoptosis, leading to neurodegeneration and cell loss in other tissues.
A comparison of the heart mitochondria in rats (4-year lifespan) and pigeons (35-year lifespan) showed that pigeon mitochondria leak fewer free-radicals than rat mitochondria, despite the fact that both animals have similar metabolic rate and cardiac output. Pigeon heart mitochondria (Complexes I & III) showed a 4.6% free radical leak compared to a 16% free radical leak in rat heart mitochondria [MECHANISMS OF AGING AND DEVELOPMENT; Herrero,A; 98(2):95-111 (1997)]. A comparison of 7 non-primate mammals (mouse, hamster, rat, guinea-pig, rabbit, pig and cow) showed that the rate of mitochondrial superoxide and hydrogen peroxide production in heart & kidney were inversely correlated with maximum life span [FREE RADICAL BIOLOGY & MEDICINE; Ku,HH; 15(6):621-627 (1993)]. A similar study of 8 non-primate mammals showed a direct correlation between maximum lifespan and oxidative damage to mtDNA in heart & brain. There was a 4-fold difference in levels of oxidative damage and a 13-fold difference in longevity, supportive of the idea that mtDNA oxidative damage is not the only cause of aging {THE FASEB JOURNAL; Barja,G; 14(2):312-318 (2000)}.
Nuclear DNA damage due to mutagens more readily leads to cancer, but defective DNA repair more readily leads to aging. It may be that mutagens damage both nDNA as well as cellular defenses against nDNA damage, but that when nDNA repair is defective cells can respond by inducing cellular senescence or apoptosis -- preventing cancer, but accelerating aging. Nuclear DNA in the brain tissue of old mice accumulates 8-OHdG/8-oxoG at nearly four times the rate of young mice {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Hamilton,ML; 98(18):10469-10474 (2001)}.
If defective mitochondria which produce high levels of free radicals are the major source of DNA aging damage, then the most effective step towards slowing aging would be improving lysosomal function by providing more efficient enzymes to the lysosomes so that the defective mitochondria can be efficiently removed -- ie, strategy (5), which seems more achievable in the short run than strategy (6). Aubrey does not include replacement of whole organs in his list, but it should be used in conjunction with strategy (1).
In sum, tissue & organ replacement are probably the most achievable strategies for rejuvenation in the short term. And lysosome enzyme enhancement is probably the most efficacious & achievable strategy for rejuvenation & slowing of aging on the level of cells & macromolecules.
