Aging-related functional declines are thought to be caused by hallmark biological processes that ultimately compromise 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 in the context of endurance training (ET) and later we established it with resistance training (RT). We propose the innovative, but logical, strategy to use combined ET and RT aligned with HHS guidelines to maximize health benefits in aging adults. 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, our 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. While sources of IRH are a constellation of modifiable and non-modifiable factors, we will test the hypothesis that factors central to aging itself – aging hallmarks such as proteostasis, mitochondrial energetics, inflammation, and circadian clock function – 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. We 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, we 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. Specific Aim 1: Interrogation. In SMART Phase I, N=200 participants stratified by sex and age group (60-69 vs ≥70 y) will enable testing of both as biological variables. After 12 wk of ET+RT including acute response studies, individual responder classification will be defined by MCIDs for CRF and fMQ. The impact of aging hallmarks (muscle proteostasis, mitochondrial function, inflammation, circadian clock function) will be determined, and we will decipher the multidimensional circuitry of IRH via integrated modeling of: (i) targeted cellular/molecular outcomes; (ii) inter-tissue communication; (iii) epigenomics; (iv) free-living behavior; and (v) clinical outcomes. Specific Aim 2: Mitigation. In SMART Phase II (10 wk), individuals not attaining one or both MCIDs will undergo an additional 10 wk of training with targeted augmentation. Those attaining both MCIDs in Phase I will be randomized to: (i) continue the supervised training; or (ii) return to free-living. The latter wil...