Aging-related functional declines are thought to be caused by hallmark biological processes1 that ultimately manifest in physical, mental, and metabolic impairments - compromising healthspan and quality of life (QoL). Exercise is a multipotent treatment with promise to mitigate most aging hallmarks, but there is substantial variability in individual exercise responsiveness. This inter-individual response heterogeneity (IRH) was first identified and extensively interrogated by Bouchard and colleagues in the context of endurance training (ET). Subsequently, the investigators have demonstrated resistance training (RT) IRH and have studied potential IRH mechanisms. The investigators then led multiple trials in older adults examining dose titration, adjuvant nutrition or medication in attempts to lower poor response rates. Many knowledge gaps remain as summarized in the National Institutes of Aging (NIA) workshop on IRH seeding this Requests for Applications (RFA). The investigators have assembled an interdisciplinary team to address the RFA's central goal, "to better understand factors underlying response variability to exercise training in older adults." Although Health and Human Services (HHS) guidelines specify combined ET and RT to maximize health benefits in aging adults, large-scale exercise trials studying IRH (i.e., HERITAGE, MoTrPAC) have restricted participants to a single exercise mode. For this project, the investigators propose the innovative, but logical, strategy to use combined ET and RT. Low cardiorespiratory fitness (CRF, VO2max) and low functional muscle quality (fMQ; strength/muscle mass) are multi-system manifestations of the deterioration of the cellular hallmarks of aging. Importantly, both CRF and fMQ are modifiable with ET and RT. Thus, the investigators design premise is that combined ET+RT is an excellent strategy for elucidating factors underlying IRH, as it forges a path toward understanding and mitigating IRH in aging with direct translatability to best-evidence public health recommendations.

It is yet to be determined how the hallmarks of aging interact to influence exercise responsiveness. For example, muscle mitochondrial energetics and proteostasis are inextricably linked, and poor responder status may be caused by lack of energetic resources to maintain proteostasis throughout an exercise program. Similarly, aging disrupts circadian clocks, leading to inflammation and disrupted cell signaling, which may also contribute to IRH.

While sources of IRH are a constellation of modifiable and non-modifiable factors, the investigators will test the hypothesis that factors central to aging itself - aging hallmarks such as proteostasis, mitochondrial energetics, and inflammation, as well as systemic and muscle-specific circadian clock function and output - are chief contributors to the multidimensional circuitry that determines whether an individual achieves the minimum clinically important difference (MCID) in CRF and/or fMQ with exercise training. The investigators will also test the hypothesis that altered exercise dosing coupled with lifestyle recommendations will promote attainment of MCIDs among older adults who do not initially respond. With CRF and fMQ as primary clinical outcomes, the investigators will use a 2-phase Sequential Multiple Assignment Randomized Trial (SMART) of combined ET+RT with clinical phenotyping and blood/muscle molecular and cellular analyses.