DOI: 10.6084/m9.figshare.29634026.v1
title: Figure 1; Figure 2; Figure 3; Figure 4; Figure 5; Table 1; Table 2; Table 3; Table 4; SupTable 1; SupTable 2; SupTable 3

description: <b>List of Figures</b><b>Figure 1.</b> <b>Mitochondrial oxidative stress and its role in age-associated osteoarthritis pathogenesis: Geroscience and nutritional implications - </b>Mitochondrial dysfunction with aging, marked by impaired electron transport chain (ETC) activity, decreased SOD2 expression, and diminished mitochondrial biogenesis, leads to excess reactive oxygen species (ROS) production and weakened antioxidant defenses. This oxidative imbalance triggers cellular stress, damaging lipids, proteins, and DNA, and disrupting IGF1 and MAPK signaling pathways critical for chondrocyte homeostasis. These molecular impairments drive chondrocyte catabolism, cartilage matrix degradation, and apoptosis, culminating in osteoarthritis (OA) progression and an ageing musculoskeletal phenotype. Within the geroscience framework, this figure underscores the relevance of targeting oxidative stress through dietary and nutrient-based interventions, such as antioxidant-rich diets, polyphenols, and mitochondrial-supportive nutrients, as a strategy to modulate mitochondrial health, attenuate cartilage degeneration, and delay OA onset in aging populations.<b>Figure 2.</b> <b>Cigarette smoking-induced endocrine and nutritional dysregulation contributing to osteoporosis: A geroscience perspective</b>- Cigarette smoking impairs bone health through multifactorial endocrine, inflammatory, and nutritional pathways. It suppresses gonadal hormones, particularly free estradiol, thereby elevating IL-6 levels and promoting osteoclastogenesis. Smoking also disrupts calciotropic hormone activity (e.g., reduced levels of 25-OH-D and 1,25-(OH)₂-D), leading to decreased intestinal calcium absorption and heightened bone resorption via the RANKL/OPG axis. Additionally, elevated adrenocortical hormones like DHEA-S and cortisol increase bone turnover and frailty. These hormonal disturbances, along with reduced osteoblast activity and impaired bone matrix synthesis (involving factors like BMP, TGF-β, VEGF, and PDGF), contribute to diminished bone mineral density (BMD) and heightened fracture risk. Within the geroscience framework, this figure illustrates how modifiable lifestyle factors, such as smoking, interact with hormonal and nutritional determinants of bone health, reinforcing the need for integrative preventive strategies. Public health approaches should target smoking cessation, nutritional optimization (especially vitamin D and calcium), and early osteoporosis screening to reduce fracture risk and support healthy skeletal aging.<b>Figure 3.</b> <b>Ethanol Metabolism and Its Age-Associated Impact on Liver Health: Nutritional and Geroscience Perspectives</b>: The enzymatic pathways involved in ethanol metabolism and the progression toward liver dysfunction with age. Ethanol (C₂H₆O) is oxidized to acetaldehyde (C₂H₄O), a cytotoxic intermediate, primarily through alcohol dehydrogenase (ADH), catalase (CAT), and the microsomal ethanol-oxidizing system (MEOS). These enzymatic reactions are cofactor-dependent, involving NAD⁺, NADPH, and H₂O₂. Acetaldehyde is further metabolized to acetate (CH₃CO₂⁻) by aldehyde dehydrogenase (ALDH), contributing to cellular redox imbalance and hepatic stress. In aging individuals, reduced hepatic enzymatic efficiency, diminished antioxidant capacity, and cumulative alcohol exposure accelerate hepatic fibrosis and mitochondrial dysfunction, predisposing the liver to steatosis and cirrhosis. Within the framework of geroscience, chronic alcohol intake acts as a modifiable dietary risk factor exacerbating age-related liver decline. These insights underscore the need for public health strategies promoting alcohol moderation, dietary antioxidants, and nutritional liver support to mitigate ethanol-induced hepatic aging and maintain metabolic resilience in older adults.<b>Figure 4.</b> <b>Canonical NF-κB activation pathway and its transcriptional role in inflammation-associated bone loss:</b> In resting cells, the NF-κB complex (typically RelA/p50) is sequestered in the cytoplasm by IκBα. Upon stimulation by pro-inflammatory signals, such as cytokines (e.g., TNF-α), oxidative stress, or bacterial components, IKK (IκB kinase) becomes activated, leading to the phosphorylation, ubiquitination, and proteasomal degradation of IκBα. This releases the NF-κB heterodimer, which translocates to the nucleus and binds target gene promoters. Coactivators and RNA polymerase are recruited, initiating transcription of genes encoding cytokines, adhesion molecules, and inflammatory mediators. The resulting mRNAs are translated into effector proteins that alter cell function, propagate inflammation, and contribute to bone resorption. Persistent NF-κB activation, particularly in aging and chronic smoking or alcohol exposure, exacerbates osteoclastogenesis and impairs bone remodeling, highlighting NF-κB as a critical target for osteoporosis intervention strategies.<b>Figure 5.</b> <b>Crosstalk between gut microbiota and bone health: implications for age-related osteoporosis</b>: Bone remodeling is a dynamic balance between osteoclast-mediated resorption and osteoblast-driven formation. This process is tightly regulated by host and environmental factors, including the gut microbiota. Age-related shifts in gut microbial composition, exacerbated by factors such as poor diet, antibiotic overuse, and declining immune function, disrupt intestinal barrier integrity and promote chronic low-grade inflammation (“inflammation”). The resultant elevation in pro-inflammatory cytokines (e.g., TNF-α, IL-6) enhances osteoclast activity and suppresses osteoblast differentiation, tipping the balance toward net bone loss. Simultaneously, gut-dysbiosis alters calcium and nutrient absorption, impacts endocrine signaling (e.g., IGF-1, PTH, serotonin), and impairs immune regulation, collectively accelerating skeletal deterioration. This figure highlights the systemic consequences of microbial imbalance and underscores the therapeutic potential of probiotics, dietary interventions, and microbiome-targeted strategies in osteoporosis prevention and management.<b>Figure 6. </b>TNF-α-driven mitochondrial dysregulation and signaling crosstalk linking inflammation, apoptosis, and osteoarthritis pathogenesis in aging: Upon TNF-α binding, TNFR1 and TNFR2 initiate divergent but intersecting signaling cascades. TNFR2 activates TRAF2, facilitating the recruitment of NIK and IKK, culminating in NF-κB activation and transcription of pro-survival and pro-inflammatory genes. Simultaneously, TRAF2 interacts with mitochondrial ROMO1, maintaining mitochondrial homeostasis. Under stress or TRAF2 deficiency, these pathways shift toward mitochondrial dysfunction and excessive ROS production, a hallmark of inflammation. Parallel TNFR1 signaling through TRADD and FADD activates caspase-8 and -3, driving apoptotic cell death. TRAF2 also modulates MAPK and JNK/AP1 pathways via RIP and ASK1, amplifying inflammatory responses and catabolic effects in osteoarthritic cartilage. This integrative diagram underscores how chronic inflammation, mitochondrial redox imbalance, and apoptotic signaling converge with age to accelerate joint degeneration, highlighting potential geroscience targeted interventions through nutritional and antioxidant modulation.<b>List of Tables</b><b>Table 1.</b> Nutritional and bioactive compounds relevant to bone health in older adults: Dietary sources, recommended intake, functional roles, and implications for geroscience. The key nutrients and bioactive compounds associated with bone health are particularly important in individuals aged 50 years or older. It includes their primary dietary sources, recommended daily intake levels, bone-specific biological functions, mechanistic pathways, and intersections with geroscience hallmarks such as oxidative stress, mitochondrial dysfunction, cellular senescence, inflammaging, and impaired nutrient sensing. Clinical outcomes, including changes in bone mineral density (BMD), fracture risk, and matrix integrity, are presented alongside translational comments on bioavailability, supplementation strategies, and clinical relevance.<b>Table 2.</b> Lifestyle-based interventions for bone health in aging populations: optimal practices, mechanistic effects, and geroscience hallmarks. The lifestyle factors that potentially influence skeletal health in adults aged 50 and above. Each entry highlights the optimal practice frequency or recommendation, underlying biological mechanisms affecting bone remodelling, systemic outcomes such as inflammation, metabolic function, or mobility, and associated geroscience hallmarks like stem cell exhaustion, mitochondrial dysfunction, and epigenetic alterations. Bone-related clinical outcomes and relevant translational notes are also included to facilitate the practical integration of these findings into public health strategies or personalized medicine.<b>Table 3.</b> Hallmarks of aging and their bone-specific manifestations: associated biomarkers, mechanistic changes, and translational interventions. The aging-related dysfunctions affecting skeletal health include cellular senescence, mitochondrial dysfunction, inflammaging, and dysregulated nutrient sensing. Each entry details the bone-specific manifestations, key biomarkers, mechanistic disruptions, and potential nutritional or lifestyle interventions (e.g., senolytics, prebiotics, antioxidants). Evidence from preclinical and human studies is noted, along with prospective therapeutic strategies targeting aging-related bone fragility. The table aims to bridge basic geroscience with actionable translational pathways for age-related skeletal degeneration.<b>Table 4.</b> Comparative overview of nutritional and lifestyle interventions for bone health across age groups. Various interventions and their differential impact on bone health across three life stages: young adults (20–40 years), peri- and postmenopausal women, and elderly men (≥65 years). Each intervention is mapped based on its mechanistic rationale, ranging from anti-inflammatory, antioxidant, and anabolic pathways to nutrient signalling and muscle–bone crosstalk. The table also highlights levels of scientific evidence, limitations in clinical application, and comments on factors such as dosage, bioavailability, compliance, and safety. This comparative framework facilitates the development of age-specific preventive or therapeutic strategies for maintaining skeletal integrity throughout the aging process.<br><b>List of Supplementary files</b><b>Sup Table1.</b> Comprehensive nutrient landscape supporting bone health in aging: dietary sources, molecular mechanisms, and geroscience relevance. The key nutrients and bioactive compounds with established or emerging roles in bone metabolism, especially in adults aged 50 and above. Each nutrient is presented with its primary dietary sources, recommended intake, direct skeletal function, molecular mechanism of action, age-related deficiency risks, and connections to geroscience hallmarks, including inflammaging, mitochondrial dysfunction, impaired proteostasis, and altered nutrient sensing. This integrative approach bridges micronutrient biochemistry with age-related skeletal pathophysiology to support targeted dietary or supplementation strategies for preventing osteoporosis and promoting healthy aging.<b>Sup Table 2.</b> Global lifestyle-based practices for osteoporosis prevention: cultural adaptations, molecular mechanisms, and age-specific recommendations. Different lifestyle interventions from diverse dietary and behavioural traditions, including resistance training, fermented dairy consumption, green tea intake, and turmeric supplementation, are known to impact skeletal health through mechanisms such as Wnt activation, NF-κB suppression, SCFA production, and osteoclast inhibition. Each intervention is categorized by recommended practice, bone-specific benefit, underlying physiological pathway, implicated hallmarks of aging, age-specific recommendations, and projected long-term health outcomes. The global diversity of these interventions supports the development of personalized, culturally grounded strategies for maintaining lifelong bone health.<b>Sup Table 3.</b> Geroscience-targeted interventions and their effects on bone health: experimental models, biomarkers, and translational relevance. The interventions, spanning dietary, physical, pharmacological, natural, lifestyle, and emerging therapies, were evaluated for their impact on bone integrity through the lens of geroscience. Each intervention is categorized by its primary hallmark of aging target (e.g., inflammaging, mitochondrial dysfunction, senescence), experimental or clinical model used, key bone-specific biomarkers (e.g., osteocalcin, CTX, trabecular markers), major findings, and challenges for clinical translation. This integrative resource supports the development of age-adapted, mechanistically informed strategies to prevent osteoporosis and preserve skeletal function.<br>