The preconference "Late-onset intervention against aging: Tools, approaches, impact was organized by Aubrey de Grey.
Prospects for Retarding Aging
Some of the opening-day sessions were devoted to those few interventions based on perturbing metabolic determinants of aging to have demonstrated some benefit in experimental animals when initiated during a similar late-life period. The results of these studies have buoyed the field with enthusiasm for the promise, but the sessions reminded researchers of the limitations and contradictions intermingled in the results. Dr. Z. David Sharp of the Barshop Institute for Longevity and Aging Studies reviewed and updated the National Institutes of Health's Interventions Testing Program (ITP)'s two lifespan studies on the mammalian Target of Rapamycin (mTOR) inhibitor rapamycin (sirolimus/Rapamune®), and the ongoing studies to evaluate "healthspan" in treated animals. Intriguing findings included the similarities and differences in the metabolic effects of rapamycin as compared to other "gerontological" interventions in the aging process, of which rapamycin is widely assumed to be a pharmacological "mimetic."
Thus, for example, the most likely mechanism of rapamycin's ability to retard biological aging is through inhibition of mTOR activity, which is thought to contribute to the slowing of age-related degeneration by reducing synthesis of defective proteins, increasing their autophagic degradation, and retarding the rate of cell proliferation (and thus dysplasia and possibly abberant differentiation of cells with age). Recent studies have confirmed that Calorie restriction (CR) and mutations that dampen insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS), also elicit a net reduction in mTOR activity, albeit with some differences in the effects on different parts of the overall pathway. Yet methionine restriction, the only dietary intervention clearly shown to retard aging independent of Calorie intake, has no effect on mTOR.(5) Again, while CR opposes the age-related downregulation of major urinary protein-1 (MUP-1), and rapamycin actively upregulates it, the gene is downregulated in mice with disruption or knockout of the growth hormone receptor gene (GHR-KO) (6)-- and rendering human translation even more confused, mice have ~40 isoforms of the gene, while humans have only one (and this one isoform is itself thought to be a pseudogene). And while increased insulin sensitivity, reduced adiposity, and lower fasting glucose levels are amongst the most robust effects of CR, both rapamycin and some IIS mutations lead to impaired glucose tolerance and a surprising increase in adiposity. Granted that, as Dr. Sharp acknowledges, rapamycin itself is not suitable for use as a human "anti-aging" agent, the fact that prominent age-retarding interventions have so complex a mixture of convergent and divergent effects on major putative effector mechanisms highlights the perils of attempting to translate such findings into therapies for human use.
My [Michael Rae's] own presentation at AGE focused on the evidence on the effects of Calorie restriction in animals, and the prospects for its human translatability, either as a dietary regimen or as harnessed mechanistically through pharmacologic "mimetics." CR was long thought to be ineffective when initiated late in life in experimental animals, but the studies on which this conclusion was based used inappropriate experimental designs. It was only in 2004 that Dr. Stephen Spindler of the University of California Riverside first applied methodological strictures already shown to be necessary to achieve robust life extension even in middle-aged mice, to animals already entering the "knee" of the cohort survival curve. (7) This study for the first time demonstrated that a careful protocol of gradual imposition of CR, using a diet with reduced energy content but the full nutritional contents (including protein) of an ad libitum diet, could indeed extend the remaining life expectancy and retard age-related disease.(7) While the absolute gains were not as great as could be achieved when animals are placed on CR as weanlings or young adults, the increase in remaining life expectancy were shown to be proportionate to what was elicited with an earlier age of initiation, consistent with previous findings.(8) The available evidence seems to be supportive of translatability of the CR effect in the narrow sense, even when initiated late in life, but that alone is not sufficient to evaluate the prospects for its use (or the use of mimetics) as a potential "anti-aging" therapy.
These and similar findings confirm the real but limited potential of therapies that decelerate the rate at which the aging body becomes progressively more frail and susceptible to age-related morbidity and mortality, particularly when administered to persons whose bodies have already suffered significant, if subtle, age-related degeneration. The majority of the sessions dedicated to late-onset intervention were therefore appropriately dedicated to progress in the development of rejuvenation biotechnologies: therapies that aim to remove, repair, replace, or render harmless the damage wrought by aging in the body, so as to restore the structural integrity and healthy function of organs and tissues. Presentations included:
• Dr. Jacques Mathieu of Rice University, presenting progress he has made in "Pre-Empting Atherosclerosis by Eliminating Stored Oxysterols." In the lab of Pedro Alvarez, Mathieu is pursuing the LysoSENS strategy of developing modified lysosomal xenohydrolases to clear out the oxidized cholesterol products whose lysosomal accumulation in macrophages underlies atherogenesis. This has included the isolation and cloning of lysosomal hydrolases from Rhodococcus jostii RHA1, the characterization of its major products, and the identificationof small molecules and components of the autophagic machinery capable of replicating aspects of these effects.
• Dr. Zhenyu Ju of the Institute for Aging Research at Hangzhou Normal University College of Medicine reported defects of haematopoiesis in wild-type mouse haematopoietic stem cells (HSC) when transplanted into late-generation telomerase RNA component knockout mice, related to defects in the systemic environment and bone marrow stromal cells in these animals. However, these defects were substantially ameliorated (and animal survival partially normalized) upon deletion of Exo-1, involved in cell cycle arrest and DNA damage signal induction. These defects will need to be eliminated to allow transplanted, telomere-replete HSC to support health and survival in humans with short telomeres due to aging in the HSC niche.
•Dr. Megan Smithey, from Dr. Janko Nikolich-Zugich's lab at the University of Arizona's Arizona Center on Aging, on results to date in SENS Foundation-funded research aimed at developing preliminary evidence of rejuvenation of the aging immune system, by modeling the benefits of purging defective, aging T-cell clones from the immunological "space," along with tissue engineering of a rejuvenated thymus -- in this case, with the use of growth factors as a proof-of-principle. The results have been limited and difficult to interpret, as it has proven difficult to develop suitable models of both immunosenescence and an appropriate test infection, and there appears to be a highly heterogeneous functional response to growth-factor induced increases in thymic cellularity; future work would incorporate lessons learned during this initial pilot.
• Dr. Shay Soker of the Wake Forest Institute for Regenerative Medicine (WFIRM), reviewing a range of his work with WFIRM Director Dr. Anthony Atala and others, including their use of the decellurized tissue scaffold technique pioneered by Dr. Doris Taylor of the Stem Cell Institute at the University of Minnesota. We have highlighted Dr. Taylor's work, and ongoing progress with the decellularized scaffold technique, ever since we invited her to present her results prior to publication at the Foundation's 2008 Understanding Aging: Biomedical and Bioengineering Apporoaches conference at UCLA, including similar results with reseeded decellularized lungs and liver; Dr. Soker's presentation highlighted his group's significant advance in the use of this system to engineer a highly functional neo-liver in a rodent model last year,(9) and the prospects for the further developments in tissue engineering using this technique and others. As will be highlighted at SENS5, his colleague Dr. John Jackson, also of Wake Forest, has already made some progress in applying the same technique to the engineering of a transplantable thymus, as a means to help rejuvenate the aging immune system, and is now receiving SENS Foundation funding to expand this project, with the anticipation of moving rapidly on to larger malmmalian systems.
• Dr. Jan Vijg, Chair of Genetics at Albert Einstein College of Medicine and the most prominent and productive investigator of the accumulation of nuclear genome mutations with aging, presented work underway (also funded by SENS Foundation) in confirming or ruling out the accumulation of epimutations as a contributor to aging within the confines of present-day lifetimes. While previous research has documented significant changes in methylation status of a number of genes in human brain during aging, these results have not discriminated alterations down to the single-cell level and have only been able to clearly document the similar changes in dynamically-regulated changes in gene methylation status across many cells in the tissue, likely reflecting an adaptive response to the aging environment. Dr. Vijg's new work exploits a novel technique, pioneered by graduate student Silvia Gravina, in analyzing bisulfite conversion of unmethylated cytosines into uracil at the level of the single-cell genome, to reflect cell-specific, genuinely stochastic aberrant methylation events. Using this method, Dr. Vijg and Gravina are evaluating the rate of epimutation in the brains of aging mice. Ruling out age-related (epi)mutations as a cause of a "generalized cellular malaise" so widespread in the constituent cells of aging tissues that they lead to the dysfunction of the tissue (as opposed to their well-established role in carcinogenesis) is critical to advancing with confidence with an ultimate cure for cancer.
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