Study of Longitudinal Aging in Mice

National Institute On Aging

Investigators

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Abstract

Aging is a biological process characterized by time-dependent functional declines that have been associated with a number of physical and mental conditions known to reduce healthspan, including energetic metabolism, chronic inflammation, cardiovascular dysfunction and cardiovascular diseases as well as neuronal dysfunction (1). At NIA, the Baltimore Longitudinal Study of aging (BLSA) is aimed at characterizing physical, functional and cognitive changes that occur with aging independent of disease development as well as the mechanisms by which disease can affect the emergence and progression of age-related phenotypes. To date, the evidence is insufficient to tell whether mice can be used as a model organism that fully recapitulates the same physiological changes that occur in human aging. Establishing such equivalence is important to decide whether research conducted in mouse is translatable to human aging (2). Thus, we are performing an extensive longitudinal study in mice to identify those biomarkers that change with aging both in mice and in humans and those that in both organisms predict disease onset and survival. An initial cross species comparison between mice, non-human primates (NHPs), and humans demonstrated the similarities and differences between age related changes common metabolic parameters (body weight, body fat, and fasted blood glucose). This work demonstrated that contrary to what is seen in humans and NHPs, blood glucose values go down with age in mice and maintaining higher blood glucose values late in life was associated with reduced mortality risk. A follow up study evaluating how early life trajectories of these metabolic parameters can be used to predict relative lifespan is currently in preparation. Additionally, using data collected from SLAM, we have recently developed a hematologic clock for predicting biologic age based on parameters commonly measured in a clinical setting. In this work we demonstrate that animals identified as “fast agers” based on our hematologic clock have increased mortality and frailty. A similar approach was applied to human longitudinal studies of aging and a manuscript presenting these findings is currently under review. Extensive work is also being done to better understand the associations and interactions between different aging phenotypes as well as the molecular mechansisms underlying these effects. To this effect we are performing a network analysis to identify patterns between different aging phenotypes and are performing extensive molecular characterization, including transcriptomics, proteomics, and metabolomics in the serum as well a multiple tissues. A targeted evaluation of some of this data was recently published in Science, demonstrating that contrary to prior reports, serum taurine levels do not decline with and are not associated with measures of physiologic function.