Longevity Meme Newsletter, September 08 2008

September 08 2008

The Longevity Meme Newsletter is a weekly e-mail containing news, opinions and happenings for people interested in healthy life extension: making use of diet, lifestyle choices, technology and proven medical advances to live healthy, longer lives.



- The Importance of Autophagy
- The Debate Over How To Tackle Aging
- New SAGE Crossroads Podcasts
- Discussion
- Latest Healthy Life Extension Headlines


Autophagy is the process by which cells break down old and damaged components, such as the all-important mitochondria, the cellular power plants, thereby recycling the materials needed to build fresh components. Damaged cells cause problems for the surrounding tissue: if cells are less damaged and remain damaged for a shorter period of time, then fewer problems result. A higher rate of autophagy should then lead to a longer-lived organism.

This appears to be the case. Research over the past few years shows that increased autophagy occurs in a range of diverse genetic and metabolic alterations that boost healthy life span in mammals. Calorie restriction, for example, or more recent progress in manipulating the p53 gene:


"Given the level of funding and interest in calorie restriction mimetics, I imagine that the development of autophagy-enhancing drugs will proceed in the much the same way over the next few years."


The most important scientific debate of our time is not much noticed beyond the aging research community. It is over how to devote resources to create therapies to treat aging. What strategies should be followed? The majority position is made up of researchers who believe that a long, slow, and hard path towards re-engineering our metabolism to slow aging is the only viable path. The minority position consists of researchers who see that striving to repair biochemical damage to the metabolism we have is faster and more efficient.

If we want to see our own lives significantly extended, we'd better help the minority position grow larger. The path of slowing aging is fearsomely complex, a very long haul, and unlikely to help those of us reading this today live longer in any significant way. A way to slow aging that emerges 30 years from now isn't all that helpful for someone who is middle-aged today. A way to reverse the damage of aging 30 years from now is a whole different story - especially as it looks to be no harder to achieve, and quite possibly somewhat easier:


"Every biochemical component in our metabolism is a part of many different complex evolved systems - evolution loves reuse and interacting, linked feedback systems. You can't change a thing without having to worry about profound side-effects in every connected process, and the processes important to aging are right in the middle of the engines of life.

"But the modern longevity engineers, the heretical minority in the aging research community, are not taking that path forward. Rather, they use the metabolism we have when we are young as the ideal reference model, and seek to reverse all changes away from that reference model that occur with age. No re-engineering, no worrying about how change A affects systems B, C, and D - this is a straightforward repair and restoration strategy. The objective is to restore the metabolism we know works, not create some new metabolism that must be extensively tested and understood.

"That is efficiency, and the nature of efficiency in longevity research is the most important debate within the life sciences today, for all that most people know nothing of it. The result of this debate will determine how long we all live in good health."


A couple of new podcasts can be found at SAGE Crossroads. Links and commentary are in the following Fight Aging! post:


"Humanity faces many challenges this century. There are three important considerations that can help us distinguish between the challenges that are truly the biggest problems from those that are less pressing. The first is the magnitude of the harms in question. Second, is their certainty of happening. Last, is the likelihood that we could do something about them. Aging scores very high on all three of these issues."


The highlights and headlines from the past week follow below.

Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!




To view commentary on the latest news headlines complete with links and references, please visit the daily news section of the Longevity Meme: http://www.longevitymeme.org/news/

Aging Cast As Autophagy Disorder (September 05 2008)
Enhanced autophagy is clearly important in most - possibly all - of the demonstrated ways to extend healthy longevity in mammals. I noticed this paper today: "Many macromolecules under degradation inside lysosomes contain iron that [makes] lysosomes sensitive to oxidative stress. ... Apart from being an essential turnover process, autophagy is also a mechanism for cells to repair inflicted damage, and to survive temporary starvation. The inevitable diffusion of hydrogen peroxide into iron-rich lysosomes causes the slow oxidative formation of lipofuscin in long-lived postmitotic cells, where it finally occupies a substantial part of the volume of the lysosomal compartment. This seems to result in a misdirection of lysosomal enzymes away from [autophagic vacuoles], resulting in depressed autophagy and the accumulation of malfunctioning mitochondria and proteins with consequent cellular dysfunction. This scenario might put aging into the category of autophagy disorders."

Progress in Bypassing Mitochondrial Damage (September 05 2008)
Allotopic expression of genes normally found in mitochondrial DNA is a core portion of the Strategies for Engineered Negligible Senescence. It is the process of inserting a copy of vital mitochondrial genes into the cell nucleus, and then figuring out how to get the proteins produced by those genes back to the mitochondria where they are needed. This could eliminate the contribution of mitochondrial DNA damage to aging. A technique for doing all this is now demonstrated in rats: "We obtained a complete and long-term restoration of mitochondrial function in human fibroblasts in which the mitochondrial genes ATP6, ND1, and ND4 were mutated ... ND1 and ND4 are mutated in nearly all cases of Leber hereditary optic neuropathy (LHON). LHON is the most common mitochondrial disorder and is characterized by a loss of vision. ... They introduced the human ND4 gene with the mutation present in the majority of LHON patients into rat eyes. The treatment caused retinal ganglion cells (RGCs) to degenerate significantly when compared to those from control eyes and was associated with decreased visual performance. Importantly, reintroducing normal ND4 led to prevention of RGC loss and visual impairment, effectively rescuing the animals from impending blindness. ... These data represent the 'proof of principle' that optimized allotropic expression is effective in vivo and can be envisaged as a therapeutic approach for mtDNA-related diseases."

Reactive Carbonyl Species, ALEs, and Aging (September 04 2008)
Free radicals (such as reactive oxygen species) are increasingly generated with age - this is the end of a long chain of consequences that starts with damaged mitochondrial DNA. How do those oxidizing agents actually cause widespread harm to bodily systems? This paper gives an overview of one broad set of mechanisms, wherein step one is the creation of reactive carbonyl species (RCS) by free radicals: "Most of the biological effects of RCS [are] due to their capacity to react with cellular constituents, forming advanced lipoxidation end-products (ALEs). Compared to reactive oxygen and nitrogen species, lipid-derived RCS are stable and can diffuse within or even escape from the cell and attack targets far from the site of formation. Therefore, these soluble reactive intermediates, precursors of ALEs, are not only cytotoxic per se, but they also behave as mediators and propagators of oxidative stress and cellular and tissue damage. ... The causal role of ALEs in aging and longevity is inferred from the findings that follow: a) its accumulation with aging in several tissues and species; b) physiological interventions (dietary restriction) that increase longevity, decrease ALEs content; c) the longer the longevity of a species, the lower is the lipoxidation-derived molecular damage; and finally d) exacerbated levels of ALEs are associated with pathological states."

Update on the Longevity Science Amex Members Project (September 04 2008)
From the Methuselah Foundation blog: "I'm pleased to say that the pro-longevity science community rallied to vote the Amex Members Project submission "Undergrads Fighting Age Related Disease" into the top 25 projects by vote totals - and made it the most discussed project of all. Thank you! That discussion is still ongoing, by the way, and people unfamiliar with longevity research have questions about the project. Feel free to jump in and help answer them. What comes next? Well, between now and September 9th - less than a week away - the Members Project advisory panel will look at the projects, votes, and discussions, and announce the final 25. Those 25 projects will be voted on by Amex card holders to determine which 5 will be funded. ... So, all you generous folk who rounded up your friends and spread the word: we're going to do it all again for those with American Express cards starting on the 9th. We here at the Methuselah Foundation are looking forward to it!"

Submissions Wanted For Hourglass III (September 03 2008)
From Ouroboros: "The third installation of Hourglass, a monthly blog carnival devoted to the biology of aging, will appear on September 9th at SharpBrains. We are soliciting entries in the general subject area of aging and biogerontology: Topics of posts should have something to do with the biology of aging, broadly speaking - including fundamental research in biogerontology, age-related disease, ideas about life extension technologies, your personal experience with calorie restriction, maybe even something about the sociological implications of increased longevity. Opinions expressed are not necessarily those of the management, so feel free to subvert the dominant paradigm. If in doubt, submit anyway. Submissions should be emailed to [hourglass.host][at][gmail][dot][com]. (In the meantime, feel free to check out previous editions of the carnival, here and here. Hourglass IV will appear on October 14th at psique.)"

Another Regenerative Strategy For Hearing Loss (September 03 2008)
Following on from the gene therapy approach for age-related deafness mentioned a few days ago, here's a cell-based therapy via EurekAlert!: "hearing loss due to cochlear damage may be repaired by transplantation of human umbilical cord hematopoietic stem cells ... the team used animal models in which permanent hearing loss had been induced by intense noise, chemical toxicity or both. Cochlear regeneration was only observed in animal groups that received HSC transplants. Researchers used sensitive tracing methods to determine if the transplanted cells were capable of migrating to the cochlea and evaluated whether the cells could contribute to regenerating neurons and sensory tissue in the cochlea. ... Our findings show dramatic repair of damage with surprisingly few human-derived cells having migrated to the cochlea. A fraction of circulating HSC fused with resident cells, generating hybrids, yet the administration of HSC appeared to be correlated with tissue regeneration and repair as the cochlea in non-transplanted mice remained seriously damaged."

Metformin as Calorie Restriction Mimetic (September 02 2008)
This paper is illustrative of the thinking that leads to trying anti-diabetic drugs as calorie restriction mimetics: "Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. It is possible that the life-prolonging effects of calorie restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of insulin/IGF-1 signaling pathway (which resemble effects of life span extending mutations or calorie restriction) could be a perspective direction in regulation of longevity. Antidiabetic biguanides are most promising among them. Here we show the chronic treatment of female outbred SHR mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but decreased the body weight after the age of 20 months, slowed down the age-related switch-off of estrous function, increased mean life span by 37.8%, mean life span of last 10% survivors by 20.8%, and maximum life span by 2.8 months (+10.3%) in comparison with control mice." Full calorie restriction does better than that (30-40% maximum life span extension), but this is a strong argument for its effects on insulin metabolism to be one cause of enhanced health and longevity.

Another Human Longevity Gene Association (September 02 2008)
The Telegraph reports on confirmation that a class of longevity genes indentified in lower animals also has an effect on human populations: "The gene linked with better health and a longer life is called FOXO3A and although similar genes have been shown to prolong life span in other species, this is the first time that FOXO has been linked directly to longevity in humans. ... Each gene comes in two copies and the team found the longevity effect of this letter was additive: those with one copy doubled their odds of living an average 98 years ... Men who had two G copies did even better and almost tripled their odds of living nearly a century, and were markedly healthier at older ages ... We screened 213 of the long-lived participants' DNA and 402 of the average-lived, focusing on five genes ... These genes were selected for good reason because they involved in the insulin pathway and signalling, which studies of other animals have shown is linked with longevity." This doesn't tell we laypeople more than we already knew: that insulin metabolism is significant in health and longevity variations within a species.

Towards a Regenerative Cure For Hearing Loss (September 01 2008)
From ScienceDaily: "scientists have successfully produced functional auditory hair cells in the cochlea of the mouse inner ear. ... researchers specifically focused on the tiny hair cells located in a portion of the ear's cochlea called the organ of Corti. It has long been understood that as these hair cells die, hearing loss occurs. Throughout a person's life, a certain number of these cells malfunction or die naturally leading to gradual hearing loss often witnessed in aging persons. Those who are exposed to loud noises for a prolonged period or suffer from certain diseases lose more sensory hair cells than average and therefore suffer from more pronounced hearing loss. ... One approach to restore auditory function is to replace defective cells with healthy new cells. Our work shows that it is possible to produce functional auditory hair cells in the mammalian cochlea. ... It remains to be determined whether gene transfer into a deaf mouse will lead to the production of healthy cells that enable hearing."

On the Way to Controlling Telomerase (September 01 2008)
Researchers are making progress in figuring how to control telomerase, and through it influence telomeres, cancer, and aging. From EurekAlert!: researchers "have deciphered the structure of the active region of telomerase, an enzyme that plays a major role in the development of nearly all human cancers. The landmark achievement opens the door to the creation of new, broadly effective cancer drugs, as well as anti-aging therapies. ... Researchers have attempted for more than a decade to find drugs that shut down telomerase - widely considered the No. 1 target for the development of new cancer treatments - but have been hampered in large part by a lack of knowledge of the enzyme's structure. The findings [should] help researchers in their efforts to design effective telomerase inhibitors ... Telomerase is an ideal target for chemotherapy because it is active in almost all human tumors, but inactive in most normal cells. That means a drug that deactivates telomerase would likely work against all cancers, with few side effects." Long-term deactivation will cause massive issues, of course, but that's not the intent for the moment. Given new information about telomerase and mitochondria in aging, there are potentially more interesting end results than good cancer therapies.



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