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For centuries, aging was considered inevitable and immutable. Geroscience provides the conceptual framework to shift this focus toward a new view that regards aging as an active biological process, and the biological age of an individual as a modifiable entity. Significant steps forward have been made toward the identification of biomarkers for and measures of biological age, yet knowledge gaps in geroscience are still numerous. Animal models of aging are the focus of this perspective, which discusses how experimental design can be optimized to inform and refine the development of translationally relevant measures and biomarkers of biological age. We provide recommendations to the field, including: the design of longitudinal studies in which subjects are deeply phenotyped via repeated multilevel behavioral/social/molecular assays; the need to consider sociobehavioral variables relevant for the species studied; and finally, the importance of assessing age of onset, severity of pathologies, and age-at-death. We highlight approaches to integrate biomarkers and measures of functional impairment using machine learning approaches designed to estimate biological age as well as to predict future health declines and mortality. We expect that advances in animal models of aging will be crucial for the future of translational geroscience but also for the next chapter of medicine. [ABSTRACT FROM AUTHOR]

Late onset, sporadic Alzheimer's disease (AD) accounts for the vast majority of cases. Unlike familial AD, the factors that drive the onset of sporadic AD are poorly understood, although aging and stress play a role. The early onset/severity of neuropathology observed in most genetic mouse models of AD hampers the study of the role of aging and environmental factors; thus alternate strategies are necessary to understand the contributions of these factors to sporadic AD. We demonstrate that mice acquiring a low social status (subordinate) in a lifelong chronic psychosocial stress (CPS) model, accrue widespread proteomic changes in the frontal/temporal cortex during aging. To better understand the significance of these stress‐induced changes, we compared the differentially expressed proteins (DEPs) of subordinate mice to those of patients at varying stages of dementia. Sixteen and fifteen DEPs upregulated in subordinate mice were also upregulated in patients with mild cognitive impairment (MCI) and AD, respectively. Six of those upregulated proteins (CPE, ERC2, GRIN2B, SLC6A1, SYN1, WFS1) were shared by subordinate mice and patients with MCI or AD. Finally, comparison with a spatially detailed transcriptomic database revealed that the superior frontal gyrus and hippocampus had the greatest overlap between mice subjected to lifelong CPS and AD patients. Overall, most of the overlapping proteins were functionally associated with enhanced NMDA receptor mediated glutamatergic signaling, an excitotoxicity mechanism known to affect neurodegeneration. These findings support the association between stress and AD progression and provide valuable insight into potential early biomarkers and protein mediators of this relationship. [ABSTRACT FROM AUTHOR]

The brown adipose tissue (BAT) is a thermogenic organ that plays a major role in energy balance, obesity, and diabetes due to the potent glucose and lipid clearance that fuels its thermogenesis, which is largely mediated via sympathetic nervous system activation. However, thus far there has been little experimental validation of the hypothesis that selective neuromodulation of the sympathetic nerves innervating the BAT is sufficient to elicit thermogenesis in mice. We generated mice expressing blue light‐activated channelrhodopsin‐2 (ChR2) in the sympathetic nerves innervating the BAT using two different strategies: injecting the BAT of C57Bl/6J mice with AAV6‐hSyn‐ChR2 (H134R)‐EYFP; crossbreeding tyrosine hydroxylase‐Cre mice with floxed‐stop ChR2‐EYFP mice. The nerves in the BAT expressing ChR2 were selectively stimulated with a blue LED light positioned underneath the fat pad of anesthetized mice, while the BAT and core temperatures were simultaneously recorded. Using immunohistochemistry we confirmed the selective expression of EYFP in TH positive nerves fibers. In addition, local optogenetic stimulation of the sympathetic nerves induced significant increase in the BAT temperature followed by an increase in core temperature in mice expressing ChR2, but not in the respective controls. The BAT activation was also paralleled by increased levels of pre‐UCP1 transcript. Our results demonstrate that local optogenetic stimulation of the sympathetic nerves is sufficient to elicit BAT and core thermogenesis, thus suggesting that peripheral neuromodulation has the potential to be exploited as an alternative to pharmacotherapies to elicit organ activation and thus ameliorate type 2 diabetes and/or obesity. [ABSTRACT FROM AUTHOR]