Can a Useful Biomarker of Aging be Built from Very Simple Measures?
There is considerable interest in the research community in the construction of a low-cost, reliable biomarker of biological age. The intent is to use such a test immediately before and after the application of a potential rejuvenation therapy to establish how well it worked. It must therefore accurately assess overall health, mortality risk, and remaining life expectancy. Currently DNA methylation assays are a leading approach to the creation of a robust biomarker of aging, as some portions of the changing pattern of DNA methylation are a fairly good reflection of cellular reactions to the damage and decline of aging. Is it possible to produce something far less complicated, however, a biomarker that uses only existing measures of health, but that is nonetheless good enough to evaluate near future rejuvenation therapies? This is an open question, one that can be argued either way.
Mammalian aging is characterized by a gradual decline of numerous health parameters with multiple biochemical, physiological and behavioral manifestations. Several animal models have been successfully used over the last several decades to address mechanistic aspects of aging and development of age-related diseases. In most of these studies the major metric parameter for assessing pro-/anti-aging effect of genetic, nutritional or pharmacological manipulation has been the animals' lifespan. While being informative, longevity by itself however, cannot provide an assessment of the animal's health status, which, like in humans, can significantly decline at older ages and therefore reduce the quality of life. This concern is particularly relevant to research focused on developing the "healthspan"-extending pharmaceuticals, efficacy of which may not be necessarily translated in increased longevity but rather in prolongation of healthy life and require quantitative objective assessment.
Clinical studies in humans measure age-related declines in performance by quantifying the frailty index (FI), which reflects accumulation of health deficits during chronological aging. Since numerous studies have shown that many age-associated changes that occur in humans are also present in aged mice, FI was recently introduced as a measure of mouse aging to pre-clinical models. However, standardized and comprehensive approaches for FI measurements, which will address changes in a broad spectrum of physiological functions, are still missing. Here we describe the development of an alternative scoring system, based on a selected set of non-invasive quantitative and physiological parameters, which could be repetitively used in the same animal over the course of its entire lifespan. We refer to this set of parameters as physiological frailty index (PFI). After measuring 29 diverse parameters including physical (body weight and grip strength), blood cell composition, metabolic, and immune properties, we selected those that show statistically significant change with age. These parameters were used to create PFI of individual mice of different chronological age. The observed gradual increase in mean PFI values with age suggests that our approach can reliably detect the scale of age-dependent health deterioration in a quantitative manner.
We also validated our approach of PFI by testing detrimental (feeding high fat diet, HFD) and beneficial (treatment with mTOR inhibitor rapamycin) factors on animals' longevity. We demonstrated acceleration of growth of PFI in animals placed on a high fat diet, reflecting aging acceleration by obesity. Additionally, we showed that PFI could reveal the anti-aging effect of mTOR inhibitor rapatar (a bioavailable formulation of rapamycin) prior to registration of its effects on longevity. PFI also revealed substantial sex-related differences in normal chronological aging and in the efficacy of detrimental (high fat diet) or beneficial (rapatar) aging modulatory factors.