Prolonged bed rest and lifelong physical inactivity cause deleterious effects to multiple physiological systems that appear to hasten aging processes. Many such changes are similar to those seen with microgravity in space, but at a much faster rate. Head down tilt bed rest models are used to study whole-body changes that occur with spaceflight. We propose that bed rest can be used to quantify accelerated human aging in relation to frailty. In particular, frailty as a measure of the accumulation of deficits estimates the variability in aging across systems, and moves away from the traditional single-system approach. Here, we provide an overview of the impact of bed rest on the musculoskeletal and cardiovascular systems as well as frailty-related biological markers and inflammatory cytokines. We also propose future inquiries to study the accumulation of deficits with head down bed rest and bed rest in the clinical setting, specifically to understand how unrepaired and unremoved subclinical and subcellular damage give rise to clinically observable health problems.