Toward an integrative approach to translational exercise biomedicine

“Life requires movement (Aristotle quotes)”. For this long-accompanying human practice, exercise, which has also been well accepted as an active approach to promoting overall health and preventing diseases throughout life, it appears quite surprising that the underlying molecular and cellular mechanisms for its benefits remain poorly understood until very recently, despite the presence of an extensive body of research for the description of multidimensional benefits of exercise. From a historical view of scientific progress, this apparent discrepancy underscores the importance of transferring growing molecular and cellular knowledge to human practice, particularly in highlighting the translational aspect (Figure 1).

Figure 1:

Translational exercise biomedicine represents an integrative approach toward a better understanding of the human body and health.

Exercise science at the molecular and cellular scale, in a sense, can be defined as signal transduction under mechanical and metabolic stimuli. Mechanical signals such as force or tension are well known to mediate and impact various types of physiological and pathological processes, including embryonic development, tumor metastasis, and immunological recognition [1]. However, our understanding of mechanical signals in living systems lags way behind that of chemical and electric signals. As a prominent example, the first type of mechanosensitive proteins, PIEZOs, were not discovered until 2010 [2], and then their structures were determined in 2018 [3]. Likewise, the modern understanding of autophagy (Nobel Prize in 2016), a cellular process closely related to the mechanical stimulation of cells and exercise, was first established in the 1990s [4]. Not surprisingly, without such “modern” knowledge on the molecular understanding of cellular systems, the classic research on exercise in general lacks a solid scientific basis, at least at the molecular and cellular scale. As such, the classic exercise science is generally not at the precision level for translation toward personalized exercise medicine.

On the contrary, traditional Chinese medicine (TCM) and exercise (TCE) are, in principle, personalized. TCM recognizes the subtle personal differences and emphasizes the importance of understanding each individual’s unique constitutional types and meridian flow patterns. Molecular and cellular knowledge could further enhance TCM by providing insights into the underlying mechanisms of action and facilitating the development of tailored interventions based on an individual’s specific biological makeup. By tailoring treatments such as herbal remedies, dietary adjustments, acupuncture, Tai Chi, and meditation exercises, TCM/TCE practitioners generally ensure that one’s needs are individually met, making preventive healthcare a personalized experience. This holistic approach unlocks new avenues of human health and performance, empowering us to provide tailored support for overall well-being.

Combining ancient practices and modern technologies in exercise science and healthcare has no doubt shown immense potential. For decades, integrative medicine systems have utilized practices like Tai Chi, meditation, and acupuncture, which have shown a reduction of inflammation, pain, cardiovascular risks, and mortality, improved neuromuscular function and metabolic regulation, and even enhanced cancer therapy tolerance and efficacy [5], [6], [7], [8], [9]. However, it is only recently that their mechanisms and efficacy are evaluated on a more biomedical scientific basis. This might be due to a cultural emphasis on perceived scientific rigor over historical credibility. For example, a 2010 randomized trial of Tai Chi in 66 fibromyalgia patients demonstrated significantly improved symptoms and quality of life compared to a waitlist control. Although this case study was limited in sample size, it rigorously evaluated specific cognitive and movement components that are feasible for broader implementation [10]. There are over 50 randomized controlled trials revealing that Tai Chi can strengthen musculoskeletal function, boost cardiovascular fitness, and regulate immunity in older adults [10, 11]. These benefits are mediated by tempering inflammatory signals like nuclear factor kB while regulating key homeostasis signals, including cortisol [12, 13]. Additional studies have shown that intensive Tai Chi is associated with increased brain volume and connectivity strength in regions related to executive function, adding biological plausibility [14], [15], [16] and underlying downstream impacts from Tai Chi mitigating pain and opioid reliance [17].

Beyond Tai Chi, a number of elegant studies on acupuncture have provided unprecedented mechanistic insights on sensitizing acupoints [18, 19] and optimized neurotransmitter modulation mechanisms underlying electroacupuncture [20]. These contemporary acupuncture protocols can engage endogenous analgesic pathways from local tissues to the brainstem, hypothalamus, and sensorimotor cortices [21], [22], [23] with adjuvant efficacy in reducing cancer pain and chemotherapy-induced neuropathy [24, 25].

Acupuncture triggers distal signaling cascades, which deactivate maladaptive immune responses underlying complex diseases as wide-ranging as sepsis, Parkinson’s disease (PD), and aging disorders [26], [27], [28]. This exemplifies potential biomolecular mechanisms underlying traditional observations of acupuncture restoring motor coordination compromised by neurodegeneration. In 2016, a study established the correlation of acupuncture-based PD therapy with autophagy. It was observed that acupuncture on Yanglingquan (GB34) in the leg of a PD rat can distally regulate the autophagic level in the brain and promote the clearance of α-synuclein [29]. A later study employed atomic force microscopic tips to precisely control the force exerted on mammalian cells, which revealed that “nanoacupuncture” could trigger cell-specific autophagy [30].

TCM/TCE embodies the unity of man and nature. The relationship between the environment, the state of nature, and the state of the body, both the natural and the social environments, affect the human body. The exercise engages extensive interconnected physiological networks across scales, posing analytic challenges but enabling broader influence. Inter-individual variation in exercise responses [31], and heterogeneity in baseline health status contribute to polymorphic outcomes [32]. As a complex intervention, deciphering precise mechanisms linking specific regimens to particular adaptations under the context of the reductionism-dominant biology remains a hurdle. Nevertheless, systems biology provides complementary network-level perspectives, enabling the characterization of multifaceted impacts of physical activity from gene expression to the microbiome [33, 34]. The cross-disciplinary collaborations combining clinical medicine, biology, bioinformatics, and exercise science can inform predictive guidance to personalize lifestyle prescription [35].

In particular, omics technologies facilitate detailed characterization of exercise response heterogeneity down to the molecular level [36]. For example, plasma metabolomics reveals post-exercise shifts in nutrient catabolism, glycolytic potential, and redox homeostasis [37]. Lipidomic profiles demonstrate prolonged activation of remodeling, bioenergetic, and anti-inflammation pathways in endurance athletes [38]. However, narrower in scope than holistic mind-body exercise, focused interrogation of specific biomolecular networks affected by physical activity proves indispensable for determining mechanisms [35]. Clearly, by merging cutting-edge omics research with historic oriental wisdom, we might explore intricate links between our lifestyle choices and genetic composition.

Traditionally, molecular and cellular biology is mainly on the discovery and interpretation of signal pathways, which is generally a linear reductionism approach; the emergency of “non-linear” systems biology is revolutionizing our understanding of our lives that is reminiscent of the oriental holistic approach. The latest breakthroughs in PIEZOs, autophagy, and microbiome are revolutionary and offer unparalleled insights into the impact of force signals on our bodies. These concepts and technologies are crucial for healthcare professionals and researchers in advancing human physiology. By leveraging these tools, we can unlock new discoveries that have the potential to revolutionize the way we approach health and wellness. From these points of view, we are optimistic that we are now standing in the new era of translational exercise medicine. Especially, by embracing the holistic approach to health, one might empower individuals to take control of their well-being and achieve a better quality of life.