The broad objective of this program is to perform preclinical experimentation on mouse model of aging to (1) establish an aging database; (2) elucidate the possible biomarkers that strongly associated with heath span and lifespan of mouse; and (3) test promising interventions. 1. Establish a database comparable to BLSA: There is no available data that is collected throughout a lifetime of a human being. Clinical longitudinal studies, even the longest running studies such as Baltimore Longitudinal Study of Aging, are consisting of observations that varied in length duo to the difficulties in long-term tracking of study subjects. There are no reports of comparable observation that done in animal models of aging either. In order to replicate the BLSA in animal models, we housed a cohort of C57 mice (n=58), male, 3 months of age, in a similar environment with free access to food and water. We used repeated echocardiography to observed cardiac and vascular physiological parameters non-invasively once for every 3 months until the natural deaths of all subjects in this cohort. We also recorded surface ECG with and without autonomic blockade (Atropine and Propranolol administration) to elucidate the changes of heart rate (HR) intrinsic HR by age. In this cohort, the median lifespan was 24 month and maximum lifespan was 30 months, and they were similar to the data published in literature. A database for a dozen of cardiovascular physiological parameters we measured repeatedly throughout the lifespan of each subject was constructed and analyzed. This is first database in this kind that provides uninterrupted observation in animal model of aging. Changes of HR and intrinsic HR in each subject showed clear age-associated changes in balance between sympathetic and parasympathetic drives. The relationship between gene expression profile of SAN and changes in intrinsic HR in the context of aging are currently under investigation. 2. Biomarkers for Aging Despite some progresses has been made in understanding of aging during last decade, there is still no physical or physiological landmarks that can be used in quantifying the aging process. Clinical studies and animal studies described some age-associated changes in human cardiovascular, neural and endocrine systems. However, validity of those changes as a biomarker for aging is still elusive. Lack of biomarker became a major hurdle in aging field since there is no way to quantify any possible beneficial ant-aging effect of potential interventions. In this study, we observed the changes of a dozen cardiovascular physiological parameters throughout the lifespan of each subject. We analyzed the trajectories of all these parameters during the lifespan. When those trajectories are plotted against a percent of lifespan that was calculated retrospectively for each individual subject, most of the cardiac and vascular physiological parameters we observed showed strikingly similar patterns. Our results may indicate that regardless of the difference in absolute lifespan of each individual mouse, all subjects would have to go through a same aging process at different speed. From these trajectories, it may possible to predict lifespan of an individual subject. Currently, the validity of those physiological parameters as potential biomarkers for aging is being analyzed.
| Yaniv, Yael; Ahmet, Ismayil; Tsutsui, Kenta et al. (2016) Deterioration of autonomic neuronal receptor signaling and mechanisms intrinsic to heart pacemaker cells contribute to age-associated alterations in heart rate variability in vivo. Aging Cell 15:716-24 |
