Abstract：In the conventional view, the major function of bone is simply providing physical support for the human body. Therefore, most of past studies in the subject focus on bone fracture in elderlies. The important questions on why bone toughness increases after fracture in young individuals, yet survival chance of elderlies substantially lowers after the same challenge remains unclear. In fact, the most important role of bone is producing stem cells and immune cells in bone marrow. Therefore, bone determines the aging rate of surrounding cells in tissues, including bone itself. In a human body, cell number develops from a single cell to 10^(13) to 10^(14) cells in adults (Bianconi et al., 2013). Most of the cells age rapidly (Spalding, Bhardwaj, Buchholz, Druid, & Frisén, 2005) where surrounding bone marrow plays a critical role for cell renewal to keep the cell population at youth level (Wang, Wehling-Henricks, Samengo, & Tidball, 2015). The brain is regarded as the most important vital tissue, in which skull bone density is ＞ 1.7 times relative to the bones in lower limbs that sustain much greater weight load (Chung et al., 2020). The main reason that brain owns much higher bone density is the prioritized demand in a human body to replace aged endothelial cells in the capillary of brain by bone marrow-derived endothelial progenitor cells. When bone density decreases, vascular aging occurs rapidly, leading to brain atrophy and dementia (Loskutova, Honea, Vidoni, Brooks, & Burns, 2009). Bone weight and density simply reflect the function of bone marrow cell production, i.e., stem cells and immune cells (Tidball, 2017). Immune cell functions to recognize and clear unhealthy cells in tissues (i.e., senescent, infected, or damaged cells). During clearance of unhealthy cells by phagocytosis, free radicals abruptly increase to attract stem cells homing into the site of damaged tissues and trigger regeneration into young cell population (Tidball, 2017). In short, the skeleton as a bone marrow cell producing organ determines age profile of tissues. Theoretically, maintaining young cell population profile of the human body forever is possible, since all human tissues are embedded with a skeleton. However, in reality, we witness inevitable aging and death of the human body without exception. The main problem lies in the structure change during growth and development, mainly the bone mass relative to body mass. When the rate of weight growth is outpacing of the rate of bone growth, an imbalanced structure (lower percent bone mass) is resulted over time. Weight gain is reflecting increases in total cell number of a human body. Bone marrow-derived immune cells and stem cells from young and old men have similar function but they are facing different environments (scale of cell population). The immune-regenerative capability is most related with the number of bone marrow cells against the cell population size in the body. Therefore, wound healing is delayed as we grow into a large cell population. With higher relative bone size against the body, tissue can always maintain younger cell age profile in the tissue. As clearance of senescent cells in tissue does not reach 100% due to such structure change, accumulation of aged cells in tissue gradually becomes reality. Thus, preventing weight growth (make cell number steady) is an essential intervention against human aging after age 20 years. However, this is difficult to accomplish since growth potential is higher in young than old tissues. Consciously preventing growth during adulthood is vital for anti-aging outcome. Exercise induces the release of bone marrow cells into circulation. This acute increase peaks at 6 h and returns to normal in 24 h (Ribeiro et al., 2017). During this process, cell renewal in human tissue occurs where aged or unhealthy cells are eliminated. The human body experiences a Darwinian natural selection against unfit cells after exercise challenges and regenerates a tissue with a younger cell population (Kuo, 2019). At the beginning of exercise, bone marrow-derived immune cells start to infiltrate into challenged tissues to recognize and eliminate unfit cells followed by stem cell homing to the site of damage for cell repopulation. This effect is closely associated with exercise intensity, which explains a higher survival rate in men participated in high physical activity compared with those in low and moderate physical activity (Byberg et al., 2009). (Full text)