Simple Assessments of Resilience as Potential Biomarkers of Aging
The search for low-cost, reliable measures of biological age continues apace in the research community. The more the better. Even if an individual measure is only loosely correlated, or produces fairly fuzzy, variable data, it may be still be possible to build an algorithm that combines many such different measures into a more accurate overall biomarker of aging. Given such a biomarker, the research community could more rapidly explore and assess potential rejuvenation therapies, and progress in the field of longevity science would accelerate as a result.
Physical resilience is the ability of an organism to respond to physical stress, specifically, stress that acutely disrupts normal physiological homeostasis. It is the ability to quickly resolve these unexpected or unusual environmental, medical or clinical challenges that should be relevant to a better understanding of the underlying health status of the animal. By definition, resilience would be expected to decrease with increasing age, while frailty, defined as a decline in tissue function and measured by parameters such as walking speed, gait, and grip strength, increases with increasing age. The loss of resilience occurs earlier in life and so may be a causative factor in the development of frailty. Therefore, assessment of resilience could be a highly informative early paradigm to predict absence of biological dysfunction, i.e. healthy aging, compared to frailty, which only measures late life dysfunction.
Unfortunately, parameters for resilience in the mouse are not well defined, and no single standardized stress test exists. Because aging is a multifactorial process, integrative responses involving multiple tissues, organs, and activities need to be measured to reveal the overall resilience status. Therefore, a panel of stress tests, rather than a single all-encompassing one, might be more informative. An ideal battery should have enough dynamic range in the response to allow characterization of an individual in easily distinguishable groups as being resilient or non-resilient. Each test should also be simple, reliable, and inexpensive so the panel can easily be duplicated by many different groups. As a panel, three stressors, cold, sleep deprivation (SD), and the chemotherapeutic drug cyclophosphamide (CYP), fit these criteria. The mechanisms of response to cold are multifactorial. SD is a risk factor for insulin resistance and diabetes, memory loss, heart disease, and cancer. CYP targets several different systems but most specifically cells of lymphoid and neutrophilic lineage.
These stressors are also relevant to human medicine and aging. For example, humans can develop intolerance to cold environmental temperatures with increased sensitivity to hypothermia with increasing age. SD is a major health concern in developed countries and is associated with increasing age. Normal aging produces sleep disturbances including sleep fragmentation and sleep loss in humans. CYP is a representative chemotherapeutic agent used extensively in patients for a variety of conditions including cancer and rheumatoid arthritis. Short-term side effects are more severe with increasing age, and intermediate and long-term effects are associated with a general accelerated aging-like state.
The resilience stressor panel described in this report represents a multisystem approach for preclinical testing of anti-aging therapeutics that could be utilized at an earlier age and more accurately than frailty assessment in the mouse. The panel is ideal because the individual stressors have a combined dynamic range in the response to allow characterization into easily distinguishable levels of resilience. Each test is simple, reliable, and inexpensive so the panel can easily be duplicated by many different groups. The stressors are also relevant to human medicine and aging. The panel therefore has the potential of being an attractive translational perturbation for resilience testing in mice to measure the effectiveness of interventions that target basic aging processes. These stressor tests, either singly or as a panel, could be adapted to humans in the clinic or in the laboratory on primary cells such as myeloid cells or fibroblasts, to approximate resilience to declining dysfunction associated with increasing age.