運動抗老化：骨髓是關鍵

Anti-Aging Effect of Exercise: Key Lies in the Bone Marrow

10.5297/ser.202009_22(3).0000

郭家驊(Chia-Hua Kuo)

大專體育學刊

22卷3期（2020 / 09 / 30）

i - iv

繁體中文;英文

傳統觀念中，骨骼最重要的功能是提供人體物理性的支撐。因此，絕大多數骨骼研究關注在高齡者骨折問題。至於為什麽幼年時骨折快速恢復並使骨骼堅韌度達到更高，高齡者骨折後卻通常活不久，過去的教科書沒有給予清楚合理的解答。實際上，骨骼最重要的功能在於骨髓，這個位置孕育了幹細胞與免疫細胞，因此骨骼這個「器官」決定了人體骨骼周圍組織的老化速度。由於成人全身擁有約10^(13)～10^(14)個龐大數量的細胞（Bianconi et al., 2013），且大部分人體細胞壽命卻很短（Spalding, Bhardwaj, Buchholz, Druid, & Frisén, 2005），全身各組織必須仰賴骨髓生產的細胞幫忙每天大量的老細胞汰舊換新，以保持組織年輕（Wang, Wehling-Henricks, Samengo, & Tidball, 2015）。大腦是人體最重要的組織。顱骨的骨質密度卻為下肢的1.7倍以上（Chung et al., 2020），儘管大腦所受到的重力挑戰遠低於下肢。大腦細胞血管的汰舊換新（例如：血管內皮細胞）的優先順序高於人體其他組織的血管。當骨密度或重量下降時所反映的是骨髓造細胞功能下降，大腦血管將迅速老化，腦萎縮／失智很快發生（Loskutova, Honea, Vidoni, Brooks, & Burns, 2009）。骨骼的重量與密度反映骨髓幹細胞與免疫細胞生產能力。這個能力充分維持，骨骼本身的重量即可維持並保持骨內細胞本身的年輕程度，骨骼周圍鄰近的組織也能跟著維持年輕，並擁有更高的生長潛力。來自骨髓的免疫細胞負責在鄰近組織內尋找、識別、清除不健康的細胞，例如：衰老、受傷與被感染的細胞（Tidball, 2017）。被免疫細胞吞噬清除過程釋放自由基分解細胞，同時吸引同樣來自骨髓的幹細胞進駐，在組織內逐漸再生出年輕的細胞（Tidball, 2017）。簡言之，骨骼所生產的骨髓細胞功能的發揮程度決定它周圍的組織內細胞的老、中、輕的結構比例，與健康程度。骨髓功能只要能快速發揮，組織損傷後疲勞發炎時間縮短，人體即可維持年輕，不致於有組織老化發生。在理論上來看，既然所有人體組織附近都有骨骼，永保細胞年輕是可能的。但為什麽我們所看到的人體終究會老化並最後死亡？主要問題出在成長過程的結構改變（即骨占全身體重的比例）。精確的說，即體重增長速度高於骨骼增長速度所造成的失衡。體重增加反映的是人體細胞新生高於死亡速度。年輕人與老年人骨髓新生的幹細胞與免疫細胞，個別來看都能發揮正常汰舊換新的功能，但兩者面對的環境規模卻不同。免疫能力好不好並不在於骨髓細胞的個別能力，而在於這一根骨所生產的骨髓細胞數量能否負擔組織內愈來愈龐大的細胞數目。在年輕時，骨骼占全身的比例較高，因此人體並不怕挑戰與感染，傷口可迅速癒合，還能因挑戰年輕化。這是因為骨髓細胞的生產速度足以應付相對規模範圍較小的細胞汰舊換新。然而，隨年齡成長，各組織細胞數目增加的速度超過骨骼內細胞成長速度時，組織汰舊換新將無法百分之百，每天累積衰老細胞而逐漸使各組織功能退化。因此，20 歲後維持體重不成長（細胞數目不增加），同時維持相對較高的骨骼重量是減緩老化最必要的作法。但這不容易做到，因為年輕的組織成長潛力較老組織高，有意識的避免成長是行為關鍵。運動可使骨髓中的幹細胞與免疫細胞迅速釋放到血液中，並在6 h到高峰，大約在24 h後回降到運動前水準（Ribeiro et al., 2017）。在這個過程中，人體歷經一次達爾文式的細胞汰弱留強，衰老細胞淘汰與新細胞再生後人體組織年輕化（Kuo, 2019）。運動後免疫細胞循環到被挑戰的組織位置對不健康細胞進行識別與清除，同樣來自骨髓的幹細胞隨後落腳在被清除的位置，在足夠的營養供應（氮與碳資源）與休息後即可完成細胞更新。當然，運動挑戰強度高低對於上述的效果可造成影響不同，解釋了為何50歲以後增加身體活動強度增加（或維持高強度），相對於降低強度者（或維持中低強度），可享有較長的壽命（Byberg et al., 2009）。

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).

1. Bianconi, E.,Piovesan, A.,Facchin, F.,Beraudi, A.,Casadei, R.,Frabetti, F.,Canaider, S.(2013).An estimation of the number of cells in the human body.Annals of Human Biology,40(6),463-471.
2. Byberg, L.,Melhus, H.,Gedeborg, R.,Sundström, J.,Ahlbom, A.,Zethelius, B.,Michaëlsson, K.(2009).Total mortality after changes in leisure time physical activity in 50 year old men: 35 year follow-up of population based cohort.British Medical Journal,338,b688.
3. Chung, C.-W.,Kuo, C.-H.,Huang, H.-Y.,Alkhatib, A.,Tseng, C.-Y.,Huang, C.-Y.,Kuo, C.-H.(2020).Highprotein supplementation facilitates weight training-Induced bone mineralization in baseball players.Nutrition,75-76,110760.
4. Kuo, C.-H.(2019).Exercise against aging: Darwinian natural selection among fit and unfit cells inside human body.Journal of Science in Sport and Exercise,1(1),54-58.
5. Loskutova, N.,Honea, R. A.,Vidoni, E. D.,Brooks, W. M.,Burns, J. M.(2009).Bone density and brain atrophy in early Alzheimer’s disease.Journal of Alzheimer’s Disease,18(4),777-785.
6. Ribeiro, F.,Ribeiro, I. P.,Gonçalves, A. C.,Alves, A. J.,Melo, E.,Fernandes, R.,Oliveira, J.(2017).Effects of resistance exercise on endothelial progenitor cell mobilization in women.Scientific Reports,7(1),17880.
7. Spalding, K. L.,Bhardwaj, R. D.,Buchholz, B. A.,Druid, H.,Frisén, J.(2005).Retrospective birth dating of cells in humans.Cell,122(1),133-143.
8. Tidball, J. G.(2017).Regulation of muscle growth and regeneration by the immune system.Nature Reviews Immunology,17(3),165-178.
9. Wang, Y.,Wehling-Henricks, M.,Samengo, G.,Tidball, J. G.(2015).Increases of M2a macrophages and fibrosis in aging muscle are influenced by bone marrow aging and negatively regulated by muscle-derived nitric oxide.Aging Cell,14(4),678-688.

1. 程瑞福,林恩賜,方怡堯(2022)。生態學模式應用於社區高齡者運動方案之介入效益。中華體育季刊，36(3)，233-242。
2. 程瑞福,林恩賜(2022)。生態學模式介入社區關懷據點對高齡者健康體適能之影響。休閒運動健康評論，11(2)，14-28。
3. 龔馬利莎(2023)。運用歷程模式發展創新成功老化高齡運動方案。嘉大體育健康休閒期刊，22(1)，79-88。