Promoting Healthy Aging: Insights on Brain and Physiological Health - A Special Issue

The special issue aims to provide insights into factors that influence healthy aging across molecular, physiological, brain, behavioral, and lifestyle domains. Regular physical activity supports healthy aging, including brain and physiological health, and helps prevent aging-related disorders such as Alzheimer’s disease (AD). During the COVID-19 pandemic, lockdowns were associated with reduced physical activity and increased sedentary behavior, contributing to deterioration in brain and physiological health among older adults. To maintain healthy aging, adherence to WHO-recommended weekly physical activity is emphasized. A recent review supports resistance training in middle and late life—at a frequency of at least three sessions per week—to mitigate neurological and cognitive consequences of aging, with insulin-like growth factor-1 (IGF-1) implicated as a key mechanism. In parallel, a drosophila study showed probiotic Limosilactobacillus reuteri extends lifespan via reduction of the IGF-1 signaling pathway, further linking lifestyle and molecular pathways to longevity.

The issue synthesizes evidence across organ systems and molecular mechanisms relevant to aging and neurodegeneration: (1) Cardiovascular aging: An overview highlights structural and functional cardiac changes, cellular mechanisms of dysfunction, genetics and epigenetics in cardiac disease, and responsiveness to exercise, supporting the sensitivity of the cardiovascular system to long-term physical activity and its role in lowering basal heart rate in aging populations. (2) Respiratory aging: Aging lungs lose elasticity and accumulate cellular damage and senescence, increasing vulnerability to respiratory infections. Clinical evidence indicates a significant burden of respiratory infections in older adults, particularly during COVID-19, underscoring prevention strategies such as exercise and smoking cessation. (3) Nutrition and cognition: Citicoline, a precursor to choline and cytidine, supports neuronal membrane integrity and myelination; oral intake improves brain choline uptake and memory indices in older adults and in mild cognitive impairment, suggesting benefits for age-related memory impairment. (4) Stress and AD: Chronic stress is implicated as a major risk factor for aging and AD, promoting AD-related pathologies and offering a window for preventive and therapeutic strategies. (5) Molecular longevity and inflammation: In C. elegans, overexpression of ATF7 suppresses aging biomarkers and extends lifespan, indicating ATF7 as a longevity-promoting factor reducing cellular senescence and inflammation. (6) Innate immunity pathways: The cGAS-STING pathway is active in multiple age-related diseases; mechanistic roles and therapeutic targeting are discussed as potential interventions. (7) Genetics and overlapping neurodegeneration: APOE, a key genetic risk factor for late-onset AD, regulates Aβ/tau pathology, inflammation, vascular integrity, glucose metabolism, and VEGF signaling; similar mechanisms appear in retinal diseases (macular degeneration, glaucoma), suggesting overlapping molecular pathways. (8) Microglial autophagy in AD: Impaired microglial autophagy contributes to inflammation, defective clearance, propagation of Aβ and tau, and synaptic dysfunction in AD; microglial receptors and autophagy regulation may inform drug development. (9) Prodromal neurodegeneration and prevention: In Parkinson’s disease, a multimodal framework targeting the prodromal period is proposed to identify at-risk individuals via symptoms and physiologic markers, stratify risk, and implement early lifestyle modifications to alter disease trajectory.

• Regular physical activity is central to healthy aging and neuroprotection; WHO-recommended weekly activity is emphasized.
• Resistance training at least 3 sessions per week in middle and late life is supported to mitigate neurological and cognitive aging consequences, with IGF-1 as a key mediator.
• Probiotic Limosilactobacillus reuteri extends lifespan in Drosophila by reducing IGF-1 signaling, linking microbiome interventions to longevity pathways.
• Cardiovascular aging is modifiable: long-term exercise regulates cardiovascular function and reduces basal heart rate, supporting brain and physiological health.
• Aging lungs exhibit loss of elasticity and increased susceptibility to infections; prevention via exercise and smoking cessation is recommended, especially given elevated morbidity/mortality in adults 65+ during COVID-19.
• Citicoline intake enhances brain choline uptake and improves memory indices in older adults and those with mild cognitive impairment.
• Chronic stress is a major risk factor for aging and AD, promoting AD-related pathology; addressing stress offers preventive and therapeutic opportunities.
• ATF7 overexpression in C. elegans suppresses aging biomarkers and extends lifespan, indicating a longevity-promoting role linked to reduced senescence and inflammation.
• The cGAS-STING pathway contributes to age-related diseases; it presents mechanistic insights and therapeutic targets.
• APOE influences Aβ/tau pathology, inflammation, vascular function, metabolism, and VEGF signaling; it also plays roles in retinal neurodegeneration, indicating overlapping pathways with AD.
• Impaired microglial autophagy exacerbates AD pathogenesis through inflammation, defective clearance, and synaptic dysfunction; targeting autophagy-related receptors may aid drug development.
• Early identification and lifestyle modification in prodromal Parkinson’s disease are advocated to reduce risk and alter disease progression.

The special issue addresses how integrated lifestyle factors—physical activity, nutrition, and stress management—alongside insights into molecular and genetic pathways, can promote brain and physiological health during aging and reduce risk for neurodegenerative diseases such as AD and PD. The convergence of evidence across cardiovascular, respiratory, and retinal systems emphasizes that systemic physiological health and neuroprotection are intertwined. Mechanistic findings (e.g., IGF-1 signaling, ATF7, cGAS-STING, microglial autophagy, APOE pathways) provide biological underpinnings for observed benefits of lifestyle interventions and identify targets for pharmacologic or adjunctive therapies. Together, these findings support a preventive, multi-domain approach to healthy aging, where early identification of risk and tailored lifestyle or therapeutic interventions can preserve function and delay disease onset and progression.

This special issue synthesizes cross-disciplinary evidence showing that healthy lifestyles—regular physical exercise (including resistance training), appropriate nutrition (e.g., citicoline), and stress reduction—support brain and physiological health in normal aging and mitigate risk for neurodegenerative diseases. Molecular and genetic insights (IGF-1 signaling, ATF7, cGAS-STING, APOE, microglial autophagy) illuminate mechanisms and potential therapeutic targets. Future research should leverage biomarkers to personalize prevention and intervention strategies in aging, integrate multi-system assessments, and test multimodal programs initiated in prodromal stages of neurodegenerative diseases.