Betaine: a promising novel anti-aging substance as an exercise mimetic

anti-aging effects. We further discuss potential barriers to the clinical translation of 23 betaine and propose strategies to accelerate the development of betaine as exercise 24 mimetic for healthy aging. Exercise refers to planned, structured, and repetitive physical activities aimed at 29 improving or maintaining health and physical fitness(1). Beyond enhancing physical 30 fitness, exercise is widely recognized as a highly effective non-pharmacological 31 intervention for preventing chronic diseases and mitigating age-related functional 32 decline(2). In metabolic disorders such as type 2 diabetes, exercise enhances insulin 33 sensitivity through GLUT4-mediated glucose uptake, thereby improving blood sugar 34 regulation and reducing complications(3). Similarly, for cardiovascular diseases, it 35 strengthens cardiac contractility, improves vascular endothelial function, and 36 optimizes lipid profiles, which in turn lowers the incidence of atherosclerosis and 37 myocardial infarction(4). Moreover, in neurodegenerative conditions like Alzheimer's 38 disease, exercise upregulates neurotrophic factors and accelerates β-amyloid clearance, 39 thus safeguarding cognitive function(5). Additionally, in chronic inflammatory 40 diseases such as rheumatoid arthritis, it modulates immune responses by reducing 41 pro-inflammatory cytokines and promoting anti-inflammatory macrophage 42 polarization, thereby alleviating symptom severity(6). Critically, the development and 43 progression of these diseases are closely intertwined with the aging process: aging 44 elevates the risk of their onset, while disease progression in turn exacerbates 45 age-related functional decline. Thus, exercise holds significant importance in 46 anti-aging. 47 The anti-aging effects of exercise are mediated through multiple interconnected 48 biological mechanisms(7, 8). Firstly, exercise enhances mitochondrial function via 49 AMPK/PGC-1α activation, boosting biosynthesis efficiency and oxidative 50 phosphorylation capacity while increasing ATP production and suppressing reactive 51 oxygen species accumulation(9, 10). Secondly, exercise exerts anti-inflammatory and 52 immunomodulatory effects by reducing proinflammatory cytokines (IL-6, TNF-α), 53 promoting M2 macrophage polarization, and enhancing regulatory T cell function(11, 54 12). Thirdly, exercise provides neuroprotection through upregulated neurotrophic 55 factors (BDNF, IGF-1), improved cerebral perfusion, and accelerated β-amyloid 56 clearance(13, 14). Finally, exercise maintains metabolic homeostasis via 57 GLUT4-mediated glucose uptake, IRS1/PI3K/AKT-dependent insulin sensitivity 58 enhancement, and AMPK-coordinated lipid metabolism(15-17)(Fig. 1) .Despite these 59 multifaceted benefits, elderly individuals often struggle to maintain exercise due to 60 physical decline, comorbidities, or environmental constraints. This limitation 61 underscores the need for exercise-mimetic interventions to harness the anti-aging 62 benefits of physical activity. 63 Recently, Geng et al. identified the renal metabolite betaine as a potent exercise 64 mimetic through comprehensive multi-omics analysis of exercise responses, offering 65 a promising solution for individuals unable to sustain long-term exercise(18).. 66 Specifically, through multi-omics analysis of 13 healthy males, Geng et al. 67 systematically characterized the differential responses to Acute exercise (AE) and 68 Long-term exercise (LE). AE primarily induced acute metabolic and immune stress, 69 marked by significant increases in non-esterified fatty acids, decreased total bile acids, 70 and upregulation of inflammatory factors including IL-6 and EN-RAGE, alongside 71 activation of the glucocorticoid receptor pathway and enhanced anaerobic glycolysis. 72 In contrast, LE triggered sustained adaptations involving metabolic reorganization, 73 immune remodeling, and gut microbiota restructuring. Metabolic reorganization is 74 achieved through the coupling of fatty acid oxidation with tricarboxylic acid cycle 75 activity, accompanied by optimized amino acid metabolism and activated antioxidant 76 defenses. Immune remodeling is reflected by increased naive lymphocytes, reduced 77 neutrophils, and attenuated lymphocyte aging via ETS1 downregulation. Gut 78 microbiota restructuring is characterized by a decrease in opportunistic pathogens and 79 suppressed lipopolysaccharide biosynthesis. Critically, LE also specifically activated 80 methionine metabolism pathways, inducing significant enrichment of the renal 81 metabolite betaine. 82 Integrated multi-omics analysis confirmed the kidney as the central organ for 83 exercise-induced betaine metabolism, mediated by upregulation of renal choline 84 dehydrogenase (CHDH). Mechanistic studies demonstrated betaine directly binds and 85 inhibits the innate immune kinase TBK1, reducing lipopolysaccharide-induced release 86 of pro-inflammatory cytokines TNF-α and IL-6 while inhibiting immune cell 87 adhesion. Murine models further established betaine's capacity to alleviate cellular 88 Geng et al. provided the first systematic analysis of the dynamic moleculal-cellular response profile of the human body to AE and LE, and found that the kidney-derived metabolite Betaine synergistically inhibits inflammation and mitigates multiorgan aging, suggesting its conducted a multi-omics analysis of AE and LE in 13 healthy males, revealing the regulatory mechanisms of AE and LE in delaying aging at the molecular and cellular levels. AE mainly triggers acute metabolic and immune stress responses, characterized by a significant 删除[Yonghui Liu]: 删除[Yonghui Liu]: 字体: (默认)Times New Roman, 小四, 字体颜色: 自动设置 设置格式[Yonghui Liu]: 字体: (默认)Times New Roman, 小四, 字体颜色: 自动设置 设置格式[Yonghui Liu]: induces more persistent adaptive changes. At the metabolic level, LE promotes fatty acid oxidation and coupling with the tricarboxylic acid cycle, enhances amino acid metabolism, and activates the antioxidant defense system. At the immune level, LE significantly increases the proportion 删除[Yonghui Liu]: Overall, AE mainly triggers immediate metabolic and immune stress, while LE drives adaptive changes through multi-systemal coordination, reducing aging and inflammatory levels at the molecular and cellular levels. 删除[Yonghui Liu]: senescence, consistently reducing established aging markers including SA-β-Gal and 89 p21. These data reveal the kidney-betaine-TBK1 axis as the core pathway 90 coordinating exercise-mediated anti-inflammatory and anti-senescence effects (Fig. 91 2). 92 To validate the therapeutic efficacy of betaine, Geng et al. conducted 93 comprehensive supplementation studies in aged murine models. They supplemented 94 aged mice with 1% betaine daily for 8 weeks and found that betaine concentrations in 95 the kidneys of aged mice increased to levels comparable to those induced by LE. 96 Functional evaluation showed that aged mice had significantly improved motor 97 coordination, muscle strength and spatial memory ability, and significantly reduced 98 depression-like behaviors. Histopathological analysis revealed attenuated markers of 99 aging, reduced lipid deposition, and reduced fibrosis in the kidney, liver, lung, and 100 skin, along with restoration of skeletal muscle morphology and epidermal architecture. 101 Molecular analysis confirmed that betaine could inhibit the phosphorylation of 102 TBK1/IRF3/p65 signaling pathway, down-regulate the proinflammatory cytokines 103 TNF-α and IL-1β, and activate AMPK/SIRT1/PGC-1α signaling pathway. These 104 collective findings support betaine as a viable exercise-mimetic intervention for 105 counteracting age-related physiological and functional decline. 106 However, we recognize that this study has certain limitations. The human cohort 107 comprised only 13 healthy young males, representing both a small sample size and the 108 exclusion of female participants. Preclinical validation was similarly restricted to aged 109 male murine models. This male-exclusive design restricts generalizability to females, 110 Geng et al. discovered that Betaine is a key molecule that mediates the anti-inflammatory and anti-aging effects of LE. By comparing the differences in plasma metabolome between AE and LE, they found that LE significantly activated the methionine metabolic pathway and 删除[Yonghui Liu]: In summary, the kidneys are the key responsive organs for the effects of exercise, targeting the inhibition of the natural immune hub kinase TBK1 by generating betaine, synergistically inhibiting inflammation and alleviating the aging process (Fig. 1). 删除[Yonghui Liu]: Geng et al. further systematically evaluated the anti-aging effects of oral Betaine supplementation in a mouse model. They administered 1% Betaine to aged mice for 8 consecutive weeks, observing their physiological functions, behavioral manifestations, and tissue 删除[Yonghui Liu]: particularly given documented sex differences in hormonal regulation, betaine 111 metabolic kinetics, and female-specific aging processes. Crucially, betaine's 112 metabolism in female physiology and its impact on reproductive systems remain 113 uncharacterized. We therefore emphasize the necessity for expanded investigations 114 with balanced gender representation and larger cohorts to comprehensively evaluate 115 betaine's effects across diverse populations. 116 We propose that betaine's most immediate translational value lies in overcoming 117 exercise adherence barriers in elderly populations. Although regular exercise 118 significantly delays aging, elderly individuals frequently struggle with sustained 119 physical activity due to age-related physical decline, comorbidities, or environmental 120 constraints(19). Betaine recapitulates exercise-mediated protection against 121 multisystem aging: preserving neurocognitive function by suppressing microglial 122 overactivation, combating sarcopenia through increased muscle fiber cross-sectional 123 area, and reducing metabolic disease risk via improved glucose-lipid homeostasis(18). 124 To advance clinical implementation, we recommend prioritizing long-term safety 125 assessments and dose-response validation in elderly cohorts, coupled with exploration 126 of synergistic formulations combining betaine with senolytic agents. These initiatives 127 constitute our strategy to establish betaine as a viable non-pharmacological alternative 128 for healthy aging promotion. 129 At the same time, we believe that betaine can be used as a fundamental candidate 130 for ovarian aging intervention research. Ovarian aging constitutes a core 131 manifestation of declining female reproductive and endocrine function, characterized 132 by diminished follicular reserve, granulosa cell senescence, and chronic inflammatory 133 microenvironments(20). Aberrant TBK1/NF-κB signaling accelerates ovarian aging 134 by promoting follicular atresia and granulosa cell apoptosis(18, 21). Given betaine's 135 specific inhibition of TBK1-mediated pro-inflammatory cascades, we propose 136 investigating its capacity to mitigate ovarian inflammation and reduce senescence 137 markers in granulosa cells. Subsequent development of betaine-based therapeutics 138 could provide targeted alternatives to traditional hormone replacement for premature 139 ovarian insufficiency and menopausal syndrome, potentially circumventing 140 estrogen-associated comorbidities while restoring endocrine homeostasis. 141 142 Fig. 1. Core exercise-induced anti-aging mechanisms. 143 144 145 Fig.2 Mechanisms of long-term exercise (LE) against inflammation and aging. 146 LE upregulates renal choline dehydrogenase (CHDH) expression to promote 147 betaine biosynthesis. Betaine further inhibited the innate immunity key kinase TBK1, 148 significantly reduced the release of pro-inflammatory factors TNF-α and IL-6, and 149 reduced the levels of senescence markers SA-β-Gal and p21, thereby inhibiting 150 inflammation and delaying aging. Fig.1 Mechanisms of long-term exercise (LE) against inflammation and aging. LE can up-regulate the transport and transformation of choline dehydrogenase CHDH in the kidney and promote the endogenous synthesis of betaine. Betaine further inhibited the innate immunity key kinase TBK1, significantly reduced the release of pro-inflammatory factors TNF-α and IL-6, and reduced the levels of senescence markers SA-β-Gal and p21, thereby inhibiting inflammation and delaying aging.