Previous sessions have focused on intrinsic sources of aging and genetic manipulations that can alter the life history. This session is devoted to external treatments and their effect on lifespan.
Richard Miller started out by describing the Intervention Testing Program, a long-term study in which mice at three centers (Jackson Labs, University of Michigan, University of Texas) are subjected to a variety of chemical treatments and then allowed to live out their lives. So far, early cohorts have showed some signs of successful longevity enhancement with anti-inflammatory drugs and rapamycin, but none so far with with antioxidants. Miller discussed in detail issues arising with experimental design, statistical power, and interpretation of data.
Hugo Aguilaniu started from the observation that calorie restriction’s effect on lifespan is reversible — thus, short diets don’t do a good job of extending lifespan. But what factors govern the reversion from the CR metabolic state to the normal-diet state? Aguilaniu’s lab has identified a kinase required for the transition: worms that lack this enzyme can reap the benefits of temporary CR for far longer than wildtype worms.
Gil Blander described the application of cutting-edge systems biology to the study of calorie restriction. Briefly, his group plugged CR-induced “state changes” (statistically significant changes in gene expression) into a large database of causal connections harvested from the literature. The database system then automatically generated hypotheses about the mechanisms of CR, and even proposed experiments (!). In the future, this approach will recommend drug targets and even lead compounds for development. For more information about the system (but not a ton more, since it’s a corporation protecting their proprietary methods), check out the Genstruct web site.
Dena Cohen proposed a SIRT1-targeted therapy for Huntington’s disease (HD), motivating the idea by demonstrating a connection between SIRT1 and HD pathology. Overexpression of SIRT1 rescues the shortened lifespan and neurodegeneration phenotypes of a mouse model of HD – though curiously it does not improve motor performance in the HD mice. Conversely, knocking out SIRT1 in the brain results in a worsened HD phenotype. What’s the mechanism? Unknown, but Cohen hypothesized that SIRT1 may regulate brain-derived neurotrophic factor (BDNF), which acts as a survival signal for neurons that are particularly vulnerable in HD.
Eric Greer (from Anne Brunet’s lab) discussed multiple methods of calorie restriction, and the differing genetic requirements for life extension induced by several of them. He argued that, at least in the worm, not all DR regimens work via AMPK and FOXO; likewise, the requirement for sirtuins is not universal to all methods of CR.
Stephen Spindler (current Mprize record holder for mouse rejuvenation) started off with the refreshing title “Searching for longevity therapeutics”. He discussed a variety of strategies to identifying lifespan extension drugs, as well as some of their shortcomings, and then proceeded to describe aging-intervention studies currently ongoing in his lab. The project is testing a variety of CR mimetics as well as orally bioavailable rapamycin, green tea flavonoids (which inhibit fatty acid synthase), a histone deacetylase inhibitor, and microencapsulated curcumin. Also on the list are statins, AGE breakers, omega 3 fatty acids, and old standbys of the life-extension movement like DHA, Juvenon (cartinine/lipoate), and resveratrol. No results yet, but we’ll be eagerly awaiting the outcome of these studies.
In the questions after Steve’s talk. Lenny Guarente suggested that because Spindler’s study focuses on a single mouse strain that typically dies of one of a small number of tumors, the lifespan studies might simply be discovering anticancer drugs. With characteristic dryness, Rich said something very much like: “Well, of course we’re not at all interested in compounds that prevent cancer, so that would be a disaster.” Miller then went on to point out that since cancer is a disease of aging, slowing the aging process would certainly delay the onset of tumor formation. Hence, even in a mouse with a very narrow range of causes of death, it would still be enlightening to look for drugs that delayed those forms of mortality.
Wolfgang Maier described the ways in which sensory detection food sources and other environmental cues (via olfaction and gustation) can control longevity in worms. (We already know something about how this works in flies.) Maier’s group has identified a neuropeptide receptor mediates sensory influences on lifespan, as well as specific saccharide molecules on the surface of bacteria that differentially activate this receptor.
Kevin Pearson, from the NIA, talked about the effect of maternal diet on offspring longevity, addressing the question of whether you are what your mom eats. Counter to predictions, he showed that two longevity-enhancing treatments of mothers (voluntary exercise and CR) both had negative consequences on offspring lifespan.
Matthew Piper asks, “What causes insulin mutant flies to live long?” He noted that the transcriptome of long-lived mutant flies resembles that of flies responding to phenobarbital, and hypothesized that xenobiotic resistance is related to lifespan extension. He has identified a transcription factor involved in detoxification reactions that increases longevity when overexpressed.
Closing up the session was Ellen Robb, who has been studying the mechanisms by which resveratrol confers resistance to oxidative stress. The compound does not rely exclusively on its inherent antioxidant activity — low doses of resveratrol massively induce manganese superoxide dismutase (MnSOD) in specific tissues (brain, but not liver) and under specific dietary conditions (curiously, only under a high-fat diet). In questions, Lenny Guarente pointed out that resveratrol is not generally believed to cross the blood-brain barrier, but wondered whether a high-fat diet might somehow allow it to do so. (Resveratrol is hydrophobic but probably quite fat-soluble…)
Session index:
Ouroboros 
that was very informative; thank you for taking the time to write about the session(s)!
Thanks for a great series of posts. I am sure it was a lot of work – but it really helped the rest of us that were not lucky enough to attend.
thanks again