By Vince Giuliano
Mainline scientific theories may have long lifespans but are inevitably overturned as accumulating evidence renders them obsolete and brings alternative theories to the fore. We saw this in physics over 100 years ago when relativity theory and quantum physics supplanted classical mechanics on the very small and very large scales. We saw this in biology starting some 150 years ago when many diseases became explainable not in the established terms of “spontaneous generation” but instead in terms of germs and then viruses. When such a major change in paradigm happens there is usually a period of significant and often bitter controversy between scientists seeking to hold on to the theories of the older paradigm and those espousing the newer one. This is followed gradually by changes in basic thinking patterns and a subsequent long period of fertile discovery.
Victor’s recent blog entry End of the free radical theory of aging and negative consequences of indiscriminante antioxidant supplementation points to a basic change in paradigm related to what was long-held to be a fundamental theory of aging, the free radical theory of aging proposed by D. Harman 45 years ago.
As Victor pointed out, a few earlier posts in this blog have telegraphed that all is not well with the free radical theory of aging. These posts include The free radical theory of aging. Is it really a theory of aging?, The anti-antioxidant side of the story and Another possible negative for antioxidants.
When I drafted my treatise ANTI-AGING FIREWALLS – THE SCIENCE AND TECHNOLOGY OF LONGEVITY in 2007, I set out to list the major theories of aging, and the first one listed was Oxidative Damage. I did that because at the time it was regarded to be the most classical and most widely-accepted theory of aging, holding that aging is the result of accumulative damage to tissues due to oxidative damage created by free radicals. I now will be revising the discussion in the treatise to be consistent with Victor’s blog entry and acknowledging the great deal we don’t know regarding antioxidant supplementation.
In the old oxidative damage framework, free radicals were seen as evil entities that created damage and accelerated aging. And people sought to stamp them out and live longer by taking antioxidant supplements Now we are in the midst of broadening our perspective to include acknowledging the positive roles free radicals play in crucial physiological processes, including signal transduction, cell-cycle regulation, and immune function. Indiscriminant taking of antioxidant supplements could interfere with critical processes and could be health damaging, even dangerous. This is a key message in Victor’s blog entry. And it is coming just at a time when the public is becoming familiar with the rudiments of the free radical theory and breakfast cereals, skin creams and a variety of other consumer products are being advertised as containing antioxidants. Everybody seems to know that antioxidants are good for you without question and contribute to longevity. Everybody, that is, except those who are really in the know and have their doubts.
So, we need to rethink deeply the whole issue of antioxidant supplementation. What seemed simple becomes very complex. For one matter, whether a substance is an anti-oxidant or not may not may be of secondary or of no importance to the key biological activities of that substance. There are hundreds of antioxidant substances just like there are hundreds of brownish supplement substances. But being brownish or an antioxidant may not be critically important or even relevant when considering the biological activities of that substance. A great many supplements in my suggested anti-aging firewall are anti-oxidants, but they are on the list for other reasons. Blueberries, for example are commonly touted as good for you because they are excellent anti-oxidants. Actually, they consist of complex phyto substances that act through a multiplicity of channels, and do produce a myriad of documented positive health impacts(ref)(ref). Olive oil, walnuts, dark chocolate, hot peppers, ginger, curcumin, resveratrol, green tea, caffeic acid, rosmarinic acid, grape seed extract, bitter melon, garlic, boswellia serrata are similarly plant-based phyto-substances with documented positive health impacts that happen also to be anti-oxidants. And there are several additional supplement substances that are much more than antioxidants as well, like l-carnosine, PQQ and lycopene.. Each acts through its own biological channels and saying that they are the same because they are antioxidants is like saying that they are the same because they are brownish powders in capsules.
It is no longer a sweeping game where antioxidant = good and radicals = bad. And I am not convinced that exogenous antioxidant supplementation is always bad. It is a much more complex situation in which antioxidant activity of a substance may be secondary or tertiary in its importance compared to other properties such as pathway activation, inhibition of NF-kappaB, epigenomic impact on methylation or histone acetylation, etc. In some cases such as major exposure to radiation, taking a strong mix of antioxidant supplements is probably well justified(ref).
Dozens of substances in my suggested anti-aging firewall regimen are incidentally antioxidants but most are not in the regimen for that reason. My intent was to only include substances with research-demonstrated health impacts. I don’t care if blueberries, green tea, curcumin, resveratrol, etc. are antioxidants given ample research that the net effects of these substances are health-positive.
It looks now like I have to look at some of my firewall substances and combinations of such substances from much more sophisticated viewpoints than I (or others for that matter) have used previously. I will be striving to adjust my suggested regimen accordingly. At present I see a need to start out by looking again at classical vitamins like vitamin C, alpha-tocopherol, and beta-carotene, asking what is really known about these substances individually in terms of current research above and beyond that they are antioxidants. This is a process that must be started now but is likely to take time measured in years before final answers become available.
My commitment in this blog continues to be reporting on and interpreting the sciences relating to aging, not to any favorite theories or even to what I may have written previously. I will be striving to update what I have written, however, and bring my treatise up to date with the paradigm shift connected with antioxidants.
First, great blog. I have been a lurker for quite some time.
Most people misinterpret the Free Radical Theory of Aging (FRTA), partly due to a lot of bad info out there. Failure of antioxidants in the blood does not harm the theory in any way. FRTA is more about the mitochondria being damaged from the inside out, look at nad+/nadh ratio and compex 1. In fact, after updates to Harman’s theory, many call it the Mitochondrial Free Radical Theory of Aging. To get actual anti-aging benefit, according to FRTA, you must rescue mitochondria, prevent the damage to them, or get the body to recognize and recycle the defunct ones.
Bruce Ames has been targeting the mitochondria recently through his research with carnitine, lipoic acid, methylene blue and others.
Sorry if you have covered this already. If you have, I missed it.
I did miss where you addressed this. I would expect that mitochondrial damage will have more effect in humans than mice, due to us having much more robust protection mechanisms elsewhere, but I do agree that it is not likely to be the perfect fountain of youth. I guess I will have to wait and see where you are taking this. Maybe moving toward focus on stem cells and telomeres. I am looking forward to it.
In this reader’s opinion, the real scientific paradigm shift is toward the telomere theory of aging. Antioxidants fit in very well with this new framework, as a means to prevent the premature shortening of telomeres — which is in large part induced by free radiacal chromosome cleavage at the tips. Strategies that boost endogenous antioxidant production, such as exercise and the use of certain supplements (like a combination of milk thistle, bacopa, turmeric, and ashwaganda, available for example in a product called Protandim) may end up playing a very important role in the new telomere paradigm. So may strategies that make judicious use of exogenous antioxidants, or that allow endogenous antioxidants to be taken orally (such as taking acetylized forms of antioxidant enzymes like acetyl-glutathione, or lypospheric forms of glutathione or catalase where the enzyme is encapsulated in a phospholipid nano-sphere, usually phosphatidylcholine, a trick used in oral chemotherapy drug delivery.)
A definitive relationship between telomere length and longevity has yet to be established. As discussed in detail by Dr. Guiliano, the regulation of telomere length is much more complex than a simple matter of the activity of a single enzyme, or ROS levels. ROS may play a role in determining telomere length, but there is certainly much more involved. What is commonly forgotten is that, even if it were possible, we would not want to have uncontrolled lengthening of telomeres in somatic cells. The shortening of telomeres in somatic, non-germline, cells is a desirable, protective mechanism to maintain genomic integrity. This is also why treatments to shorten telomeres are a central focus of anticancer therapeutics, see: Recent Patents on Anti-Telomerase Cancer Therapy http://www.ncbi.nlm.nih.gov/pubmed/21854360
What we want is to maintain telomere length in progenitor cells in order to replenish the supply of viable somatic cells. Most of the studies on human telomere length have used white blood cells, which are readily accessible. However, there is no clear relationship between leukocyte telomere length and the telomere length of general progenitor cells. Some have questioned the significance of telomere length in leukocytes altogether, since they appear to be able to selectively activate telomerase, upon demand, in response to environmental cues, including ROS. ROS are the signal transduction molecules that modulate immune cell activity, signaling the production of inflammatory cytokines and the activation of telomerase in leukocytes, as needed. So, some ROS actually serve to increase telomere length. This doesn’t mean that ROS aren’t also involved in the shortening of telomeres. Once again, it is an error to group all ROS together as one “evil” entity, when in fact there are many different types of ROS with distinct effects and physiological activities. Still, the fact that most studies to-date have measured telomere length in leukocytes calls into question the conclusions of those studies, if as appears to be the case, telomere length in leukocytes is irrelevant. We really need more telomere studies in different types of cells. See:
Length Does Not Matter http://atvb.ahajournals.org/content/31/2/235.long
Telomerase Activation http://atvb.ahajournals.org/cgi/ijlink?linkType=ABST&journalCode=atvbaha&resid=31/2/245
I should also mention that the recent new telomere support product Sierra Sciences has been working on (Product B, as marketed by Isagenix Corporation) contains milk thistle, bacopa, ashwaganda, and turmeric at the very top of its ingredient list — presumably to boost endogenous production of glutathione, catalase, and SOD. There are also tantalizing circumstantial hints in the medline-indexed literature that milk thistle and ashwaganda may mildly induce telomerase. (Any substance that shows the ability to increase stem cell proliferation and differentiation in vitro, may be doing so by inducing telomerase expression. Both milk thistle and ashwaganda have shown these properties. Search for “milk thistle telomerase” and “ashwaganda stem cells” on pubmed.)
milk thistle & telomerase:
ashwaganda & stem cells:
I have been aware of themitochondrial free radical theory of aging for some time and have followed Bruce Ames work. I have covered this to some extent not in my blog but in my treatise under the third theory of aging Mitochondrial Damage (http://www.vincegiuliano.name/Antiagingfirewalls.htm#MitochondriaDNAMutationtheory). And I have been taking the supplement combination of acetyl-l-carnitine and alpha-lipoic acid researched by Ames and his group.
I do believe that the future of anti-aging interventions lies with epigenetic activation and working with stem cells.
Vince, Was curious regarding what doses of ALC and ALA you take per day.
Interesting comment! My opinion is that the telomere theory of aging is quite flawed. I have already written about this several times. Namely, I see short telomere length as being a characteristic of cell senescence and think that in most cases age-related telomere shortening is not the key driver of cell senescence. Other things make cells act younger or older. I am particularly disenchanted with seeking to extend lives via extending telomeres using activators like the commercial astragalus-based ones. I do agree that there indeed is research evidence that some antioxidant supplements may mildly act to lengthen telomeres and myself take ashwagandha and turmeric among others. Other plant-based phyto substances like curcumin and resveratrol have also been found to have telomere-lengthning capabilities. And I take these as well. However I see such telomere enlongation as being symptomatic of a more youthfull cellular state rather than defining it. Ashwagandha and milk thistle as well as curcumin and resveratrol are very complex phyto substances and I strongly suspect that the fact that they are antioxidants is incidental to their cell rejuvinating properties, important though the impacts of taking them as supplements might be.
Thanks again for your comments.
I very much disagree with you on this. 🙂
My view is exactly the opposite.
But the fact of the matter is that the evidence is definitely not there yet to support the hypothesis that the telomere theory is ultimately fundamental and subsumes most of the other aging theories as symptoms of short telomeres, as I strongly believe. There is enough preliminary evidence though, in my opinion, to consider this hypothesis extremely promising and to provide much fuel for debate.
>> Namely, I see short telomere length as being a characteristic of cell senescence and think that in most cases age-related telomere shortening is not the key driver of cell senescence. Other things make cells act younger or older.
In my opinion, this can’t be true. Telomerizing human cells in vitro consistently and dramatically extends the Hayflick limit. That experiment was first perfomed at Geron, and has now been repeated many times. Geron demonstrated by gene chip analysis that telomerized older cells (dividing way past Hayflick) are indistinguishable from younger cells, in terms of gene expression. There is no way to tell the difference. In my view, this demonstrates that telomerase causally prevents human cell senescence, and therefore that telomeres are fundamental in human cell senescence.
I too am frustrated with astragalus-based telomere inducers, but for different reasons. These compunds are too weak to have a significant effect on aging. But in the last year, Sierra Sciences has made significant progress in discovering new small molecule inducers from natural compounds. Bill Andrews has publicly stated that Sierra has discovered at least 5 botanical extracts that induce telomerase, including a natural botanical extract that registers at 3.28 of HeLa (3.28% of the telomerase activity naturally present in an immortal cancer line!)
Presumably this strong 3.28 inducer is included in Product B, which is now available commercially. It won’t be long before they find even stronger inducers from botanicals, which they plan to include in updated formulations of Product B.
By “telomerizing”, I mean exposing cells to the telomerase enzyme.
Let me stary by saying that it was reading Michel Fossel’s book in 1994 and enthusiasm for the telomere-length theory of aging that impelled me into the aging sciences field in the first place. I have followed research in this field since then, invested in Geron over 12 years ago and am still an investor in that company. While telomere research has been extremely important I let go of the telomere-length theory of aging only very slowly and with much reluctance.
The in-vitro experiments of immortalizing cells with telomerase seemed earth shaking at the time, but after all these years I know of no research with normal mammals where life was extended due to exogenous administration of telomerase. Rather, it turns out that telomere length homeostasis is a very complex topic. If you go to my blog entry The epigenetic regulation of telomeres at http://www.anti-agingfirewalls.com/2011/03/27/the-epigenetic-regulation-of-telomeres/ you will find some of my thinking as well as links to several other blog entries I have writtem on telomeres/telomerase as well as a link to extensive discussion of the topic in my treatise.
I do confess I have not visited the state of telomerase research for a while now and, as you know, if I turn out to be wrong on this I will (unhappily) eat my words.
As far as Bill Andrew’s work I can only wish him the best outcomes. I await to see research results showing positive health benefits or longer lives due to taking product B. Even for small animals. As you probably know, I am impressed by several botanicals. I would love to hear of such results but for now remain cynical due to the TA65 and similar experience and learning about the complexity associated with cell senescence. Again, “show me the research!”
You’re 100% right. The research is still in its infancy.
Let me suggest the following self experiment:
Take Product B for a few weeks and observe the changes. If it’s anything like what I’ve personally experienced and what I’ve seen in family members (inlcuding a 97 year old), you’ll be quite shocked. I would suggest using twice the dose listed on the bottle, i.e. 4 capsules in the morning and 4 capsules in the evening. At this dose, I’m quite confident you’ll only need to do this experiment for a few weeks to make a determination.
I have a feeling this self experiment will rekindle your “enthusiasm” for the subject.
OK. I will do that.
Getting back to your question I take a pill with 500mg of ACL and 300mg of alpha-lipoic acid twice daily.
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