Molecular pathology endpoints useful for aging studies

Abstract

The first clinical trial aimed at targeting fundamental processes of aging will soon be launched (TAME: Targeting Aging with Metformin). In its wake is a robust pipeline of therapeutic interventions that have been demonstrated to extend lifespan or healthspan of preclinical models, including rapalogs, antioxidants, anti-inflammatory agents, and senolytics. This ensures that if the TAME trial is successful, numerous additional clinical trials are apt to follow. But a significant impediment to these trials remains the question of what endpoints should be measured? The design of the TAME trial very cleverly skirts around this based on the fact that there are decades of data on metformin in humans, providing unequaled clarity of what endpoints are most likely to yield a positive outcome. But for a new chemical entity, knowing what endpoints to measure remains a formidable challenge. For economy's sake, and to achieve results in a reasonable time frame, surrogate markers of lifespan and healthy aging are desperately needed. This review provides a comprehensive analysis of molecular endpoints that are currently being used as indices of age-related phenomena (e.g., morbidity, frailty, mortality) and proposes an approach for validating and prioritizing these endpoints.

Measuring biological aging in humans: A quest

“…Studies in animal models have begun to reveal the nature of these mechanisms, and some assays for humans have been developed. Although many of these unique or composite measures generally track chronological age with a predictable schedule, the biology of their compensatory and homeostatic nature is only partially explained and their relevance for health is limited to observational studies (Hilmer & Le Couteur, ; Kirkland, Tchkonia, Zhu, Niedernhofer, & Robbins, ; Moreno‐Villanueva et al, ; Newman et al, ; Niedernhofer, Kirkland, & Ladiges, ; Richardson et al, ; Robbins & Niedernhofer, ).…”

Frailty and Cardiovascular Disease

“…Frail patients and patients with HF consistently have a similar biochemical proile of elevated CRP and interleukin-6, which in turn promote mitochondrial dysfunction [18,22,31].…”

“…A pro-catabolic state is frequently seen in both CHD and frailty and leads to, as we already know exists in frailty, a pro-inlammatory state [18,24]. [31]. In order to highlight the common role inlammation plays in both CVD and frailty, we can appreciate that elevations of C-reactive protein (CRP), factor VIII, and D-dimer are commonly seen even after correction of CVD [32].…”

The Role of Neuroimaging in the Ageing Brain

“…Image of the striatal dopamine transporter -DAT exams use the ioflupane iodine-123 compound to measure the presynaptic dopamine transport in the brain [27]. New molecular techniques are now under development to detect other pathological processes associated with dementia, such as neuroinflammation and deposition of tau protein [28]. Other functional imaging studies include measures of cerebral perfusion or blood flow and cerebral metabolic activity.…”