Catalyst Awardee

Project Description

Organismal Aging and Oxidants Beyond Macromolecules Damage

Marie-Veronique Clement, M.Sc., Ph.D., and Shazib Pervaiz, M.B.B.S., Ph.D., National University of Singapore

Competition Sponsor: Ministry of Health and National Research Foundation of Singapore

One prediction of the free radical theory of aging is that oxidative stress shortens organisms’ lifespan because of the damaging effect of oxidants on macromolecules, thereby resulting in loss of tissue/organ functionality as seen in age-related diseases. Based on this prediction, observational studies and small interventional studies accumulated to justify large-scale double-blind interventional trials of antioxidants for many age-related diseases. Unfortunately, by early 2000, sufficient clinical evidence had accumulated to indicate little to no significant health benefits of supplementation with antioxidants. Notably, age-related decline in health and organ functions is also linked to the accumulation of IL-6 secreting senescent cells. While, most interventions using anti-oxidant to benefit human health appear to target oxidants that are implicated in macromolecule oxidation, primarily hydrogen peroxide (H2O2), our recent in vitro work provides evidence for a distinctly different redox milieu involved in the phenotype of senescent cells. We have identified a superoxide/nitric oxide (O2-/NO)-driven redox state which has an effect different from H2O2 on the secretion of the senescence-associated interleukin, IL-6. While inhibiting O2-/NO signaling mitigated IL-6 secretion, scavenging H2O2 increased it. Based on these data, we hypothesize that two distinctly different redox states are at play as the stimulus for human aging. Hence, we propose that for an anti-oxidant approach to have significant benefits on human life-span the antioxidants and/or redox modulators used should mitigate not only the damage to macromolecules but also the accumulation of senescent cells with an age-associated phenotype. As such, this project intends to generate data to get a deeper understanding of the newly discovered redox state in age-related cellular senescence. Moreover, going forward, these results will enable us to establish a cell-based model system that could be used to screen novel redox modulators, able to mitigate both macromolecules oxidation and the accumulation of age-associated senescent cells.

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