The 2018 Nathan Shock Centers’ Summit: A Summary
by Steven N. Austad, PhD; Co-PI, Nathan Shock Centers Coordinating Center; Director, Nathan Shock Center at University of Alabama Birmingham
The biennial Nathan Shock Centers’ Summit was held this year in Philadelphia immediately preceding the American Aging Association’s annual meeting. The symposium focused on three major issues in aging research: 1. the development of biomarkers of aging, 2. critically examining the healthspan concept; and 3. practical issues of translating basic science into clinical therapies.
The Development of Biomarkers of Aging
Biomarkers of aging were the focus of a major research effort by the National Institute on Aging in the 1990’s, but that research effort was universally acknowledged to have failed to uncover any satisfactory markers. Symposium organizers, the Nathan Shock Center Directors together with AFAR’s Nathan Shock Centers Coordinating Center, felt that with the development of so much “omics” biology in the past two decades, it was time to revisit the biomarkers issue. Richard A. Miller from the University of Michigan kicked off the session noting that the field needed clear definitions. He suggested that biomarkers of aging should be most usefully defined as early- or mid-life predictors of later life health rather than predictors of longevity. To the extent that such biomarkers could be developed, they would accelerate the pace of research into health-extending interventions substantially. Among other things, Miller pointed out how the stress-resistance of cultured fibroblasts showed considerable promise as biomarkers.
Dr. Eline Slagboom from Leiden University had also focused on biomarkers of aging in humans the evening before during her keynote address to open the symposium. She described a very ambitious project in the Netherlands called the Biobanking and Biomolecular resources Research Infrastructure, which was providing access to biomaterials, blood and tissue samples, as well as images, from longitudinal studies going on throughout the Netherlands. Her research is focused on metabolomics and she noted that a subsample of only 14 metabolites had been shown to do better than traditional risk factors at predicting death of subjects. In fact, these metabolomics markers predicted death just about as well as epigenetic markers, currently a very hot topic in the aging biomarkers literature.
Appropriately, Steve Horvath who has brought the “epigenetic clock” to prominence in aging research, pointed out that his epigenetic clock, now a series of 391 CpGs correlated surprisingly well with age in different cell types as well blood and buccal cells. Skin fibroblasts even showed accelerated aging changes in the epigenetic clock in people with Hutchinson-Gilford progeria.
Laura Niedernhofer from Scripps Institute in Florida (and now the University of Minnesota) discussed the development of proteomic biomarkers in a variety of mouse models, noting that they had found remarkably consistent age-related changes in a panel of just 14 proteins across multiple mouse genetic backgrounds and that this panel showed reduced proteomic age in very young mice treated with rapamycin, a well-known life- and health-extending drug.
Tamara Harris explained how an inflammatory marker, C-reactive protein (CRP), had been found to be predictive of cardiovascular disease in multiple human studies, yet researchers were still wary of considering elevated CRP a proven risk-factor for cardiovascular disease, particularly as it had little specificity for the vascular system.
Finally, Kristen Fortney of BioAge Labs reported how their company had looked for metabolomic markers of mortality in samples from two large human studies. Twenty percent (20%) of lipid metabolites associated with all-cause mortality in both studies and even a single metabolite (phosphatidylcholine) had a surprisingly good correlation with mortality.
Critically Examining the Healthspan Concept
Another session in the NSC Summit focused on the healthspan concept and ways in which healthspan is defined and measured. The session opened with Harvey Cohen from Duke University enumerating the many ways physicians and epidemiologists have sought to define healthspan, using labels like “healthy life expectancy,” “active life expectancy,” or “disease-free life expectancy,” all of which address the issue, but it is not clear how these concepts would be applied to animal studies. It would certainly be desirable to have one unified definition of healthspan that could be applied not only to humans but also to various animal species used in laboratory research on aging. He also noted that one particularly human complication how to factor self-rated health into the discussion. After all, two people with very similar conditions might interpret their own health differently. How would the healthspan concept handle this – a very good question.
Colleen Murphy, a C. elegans biologist from Princeton University, noted that many worm healthspan studies had been carried out to date. These studies mainly focused on whether worms with longer lives also displayed longer health. She suggested that between studies of movement and various learning paradigms, healthspan could be nicely measured in worms and that worms with reduced daf-2, an ortholog of the mammalian insulin/IGF receptor, signaling showed superior health to wild-type worms by virtually any health metric.
Veronica Galvan from UT Health San Antonio then discussed cognitive health and the many ways to assess it in humans. She pointed out that although there were also numerous metrics of cognitive aging in mice, all were subject to various complications associated with aging such as reduced movement ability, sensory acuity, and altered motivation. She advocated for the common marmoset, a small short-lived primate and a cognitively more sophisticated species than the mouse, as a preferable animal model of cognitive health.
Rafael de Cabo from the National Institute of Aging described a large ongoing study aimed at determining similarities and differences in mouse and human healthspan measures. So far, some clear similarities as well as some significant differences between the species had emerged.
Practical Issues of Translating Basic Science into Clinical Therapies
The third major topic concerned translating animal studies into clinical therapies. Mark Bamberger from Stealth Biotherapeutics described that his company’s mitochondrially-targeted compound, SS-31, improves mitochondrial function and has moved quickly from mouse studies to human clinical trials for several age-related diseases.
Salvatore Oddo from Arizona State University then discussed several ongoing trials with S6K1 inhibitors, rapamycin, and PIM inhibitors for neurodegenerative diseases and noted among other things that a PIM inhibitor caused some toxic effects in mice.
G. Alexander Fleming from Kinexum and formerly of the FDA described a number of regulatory issues that basic scientists seeking to translate their work into human therapies should be aware of. He noted that good science alone is not sufficient to advance healthspan therapies. Solid evidence of both safety and efficacy is critical to successful translation and the cost of assembling such evidence needs to be part of any business model. He also pointed out several practical problems with avoiding FDA approval by marketing a putative therapy as a dietary supplement. Finally, he noted several regulatory difficulties specific to developing healthspan extending therapies but felt that the TAME (Targeting Aging with Metformin) study was paving the way for other successful studies.
Monica Mita from Cedars-Sinai finished up this session by discussing several analogs of rapamycin (= rapalogs) that were designed to get around a solubility problem with rapamycin. She described by intravenously administered and orally bioavailable rapalogs that were currently FDA approved for specific cancers and explained that there some small molecules in development that inhibited mTOR indirectly by targeting upstream activators.
Several speakers have agreed to share their slide presentations which can be found here.