The human biological clock and aging—a comprehensive approach integrating reductionism, holism, and geromedicine for proactive healthspan strategies

Currently, there is an array of established aging clocks that incorporate various factors such as epigenetic modifications, proteomic changes, inflammatory and immune pathways, neuroimaging techniques, and alterations related to the microbiome. These aging clocks possess significant therapeutic potential for alleviating the effects of chronic inflammation and associated diseases (Min et al., 2024).Moreover, comprehensive multidisciplinary scoping reviews pertaining to the nitric oxide (NO)mediated hypovascularity hypoxia hypothesis may illuminate the interconnected nature of biological aging clocks by integrating reductionist, holistic, and systems biology approaches. These longitudinal biological investigations are essential for elucidating persistent changes and big picture causal relationship patterns that underlie the primary biological mechanisms driving the aging clock (Phua, 2021(Phua, , 2023(Phua, , 2024)).Reductionism is characterized by the breakdown of systems into their constituent parts to analyze individual functions, whereas holism underscores the interconnectedness and emergent properties of the system as a whole (Gatherer, 2010). As the landscape of scientific inquiry progresses, there is an increasing acknowledgment of the necessity for holistic approaches that recognize the importance of intricate interactions and emergent attributes (Delker and Mann, 2017). Furthermore, a systems-based focus of geroscience is to accelerate research into the drivers of biological mechanisms that underlie aging, with the aim of developing improved clinical interventions for diseases and chronic conditions commonly experienced by the elderly population (Sierra, 2016;de Magalhães, 2024).Temporal medicine, which is inherently time-centric, examines the dynamics of disease progression over time, the effects of treatments at various stages of a patient's illness, and the influence of intervention timing on patient health outcomes (Choudhary and Fränti, 2023;Rodenkirchen, Hoyer and Brinks, 2025).Integrative medicine combines established medical practices with evidence-based complementary therapies and lifestyle modifications to improve overall health and well-being. This holistic approach is particularly effective in preventing chronic diseases and managing existing conditions (Teut and Ortiz, 2021).The future trajectory of precision geromedicine encompasses proactive, preventive, and interceptive strategies aimed at enhancing healthspan(definition) (Amalaraj et al., 2025;Kroemer et al., 2025).The concept of the biological aging clock posits that aging is an orderly and predictable process governed by intrinsic biological mechanisms, rather than merely a reflection of chronological age. This perspective indicates that aging adheres to a defined program, characterized by measurable markers that indicate an organism's age and its proximity to mortality (Palmer, 2022).In addition, the field of OMICS-which encompasses the comprehensive analysis and interpretation of multi-omics data (large datasets) representing the structure and function of biological systems at various levels-has significantly transformed our approaches to studying biological systems (Ahmed, 2022;Chen et al., 2023). This paradigm shift includes -top-down‖ methodologies, greatly influenced by the advancements in OMICS, integrated with -bottom-up‖ strategies, thereby providing a comprehensive toolkit to facilitate effective biological system investigations (Dai and Shen, 2022). The emergent characteristics of multi-omics datasets highlight a deeper understanding of the predictable biological and cellular dynamics linked to the mid-life hormonal clock associated with menopause and andropause. Furthermore, they highlight the primary aging-related NO-deficiency; a critical gasotransmitter, and micro-angiopathy; characterized by reducing microvascularity-perfusion function. Additionally, these attributes reflect the secondary cumulative pathobiology of tissue hypoperfusion, which involves hypoxia and chronic inflammation (Figure 1) (Phua, 2021(Phua, , 2023(Phua, , 2024)).The field of gerontology typically examines aging in individuals aged 65 and older (Lyu et al., 2024). It is important to note that the human biological aging clock initiates in midlife, between the ages of 40 and 60 (Levine et al., 2016;Huang et al., 2025).Consequently, public health prevention efforts should prioritize the middle-aged demographic, as it presents the greatest opportunity for intervention at the upstream level (Woods et al., 2024); coined the term -precision middle-aged geromedicine-Mid-Geromedicine‖ (Figure1).The dynamic progression of aging (Ferrucci et al., 2020), particularly concerning early-stage (induction) microvascularity-perfusion networks would demonstrate superior tissue functionality recovery in comparison to late-stage (latency) dysfunction, which is often compounded by cumulative pathobiological pathologies (Figure1) (Phua, 2024). This transition dynamism (Yang et al., 2024) is linked to the positive outcomes associated with early sex hormone replacement therapies in alignment with the timing hypothesis (El Khoudary et al., 2020;Hodis and Mack, 2022); correlated with reductions in all-cause mortality during menopause (Arayici, Kilic and Yilmaz, 2024;Liu et al., 2024) and andropause (Jaiswal et al., 2024;Yeap et al., 2024), and increased production of NO (Jokela et al., 2003;Gur et al., 2020).Furthermore, significant nonlinear multi-omics aging bursts are at 44 and 60 years of age (Shen et al., 2024), coinciding with a decline in sex hormone levels and increasing inflammation (Ketchem, Bowman and Isales, 2023;Allahverdiyeva et al., 2024;Lombardo et al., 2024) and the onset of increased multimorbidity in individuals aged 65 and older (Figure1) (Divo, Martinez and Mannino, 2014;Song et al., 2023).NO serves as a crucial empirical link between aging-related sex hormones and the vascular-aging process within the microvascularity-perfusion mechanistic ne