Aging

A comprehensive understanding of the processes of aging is crucial for human health. From birth, we are subject to the effects of aging. However, it is only in later life that the physical effects of aging become apparent. Sociologically, age is often perceived as an advantage as we become wiser and more experienced. Physically, however, we lose functionality: hearing and vision deteriorate,¹ muscles weaken,² bones and joints wear out,³ and diseases become more common. This raises the question of whether we age biologically as a result of disease, or whether the aging process itself is the cause. If the latter is the case, could aging, in the extreme, be considered a disease?

It is puzzling why closely related animal species age so differently. Some mammals, like mice, live for around 1 year, while others, like the bowhead whale, can live up to 200 years.⁴ What is certain is that our ability to regenerate decreases with age, and that aging and regeneration are linked: regeneration is optimal in the embryonic stage, acceptable in adulthood, and usually very poor in old age.^{5, 6} Different organisms exhibit varying regenerative potentials; for example, some lizards can simply regrow their limbs.⁷ What would be the implications of living more than 500 years and being able to regenerate from severe diseases and injuries? The Bible mentions Methuselah, who supposedly fathered Lamech at the age of 187 and lived for another 782 years (Old Testament (Gen 5:21–27)). Could humans theoretically achieve such longevity? If so, it would undoubtedly raise ethical issues. However, these considerations raise important questions about the biology of aging and the possibilities of regeneration, which are of great importance both to science and to our understanding of the human life cycle. Aging research has, in recent years, experienced transformative advances toward a deeper understanding of the molecular and cellular mechanisms of the aging process. Aging can be understood as a physiological process characterized by the degradation of biomolecules and the accumulation of damaged cellular components. As we age, the efficiency of mitochondrial function, critical for cellular energy production, diminishes, leading to a reduction in energy output; this decline is intricately connected to cellular senescence, where cells permanently halt division but remain viable, while telomere length, which shortens with age, is closely tied to cellular aging and senescence.⁸ Aging is commonly perceived as a consequence of wear and tear, where accumulated damage over time leads to gradual physiological decline. Nevertheless, the notion of reverse aging, where exercise and interventions might rejuvenate tissues and restore youthful function, is gaining momentum, with research focusing on unraveling and manipulating the underlying mechanisms of aging. Significant progress has been made in elucidating the roles of senescence, telomere dynamics, and mitochondrial function in aging, paving the way for novel therapeutic strategies.

This paper presents a summary of recent findings in the field of aging research, with a particular focus on the key mechanisms linked to age-related diseases, highlighting some recent breakthroughs in aging research and innovative approaches that promise to aid our ability to combat the effects of aging and improve the quality of life for the aging population.

Degenerative diseases, not only those affecting the nervous system, share common mechanisms independent of their etiology or site of disease pathology.⁹ Recently, a number of studies have contributed to elucidating the underlying pathomechanisms of neurodegeneration. Zhang et al.¹⁰ contributed to identifying a new factor in autoimmune-mediated neural degeneration, while Tomaz et al. show how muscle regeneration is inhibited in muscular degenerative disease.¹¹ Protein aggregation indicates of a decline protein quality control and proteasomal degradation, linked to aging and disease.¹² At the structural interface of cognition and skeletal muscle control, noradrenergic brainstem neurons are susceptible to the deposition of damaged proteins, leading to cell death both in age-related and early-onset neurodegenerative disease.¹³ As populations age, the incidence of degenerative diseases such as Parkinson's disease is sharply increasing.¹⁴ The commonalities between degenerative diseases may provide exciting collaborative research opportunities to address the burden of degenerative diseases, starting with (i) detection and tracking/imaging technologies and (ii) translatable model systems for preclinical testing of therapeutic approaches.⁹

Physical exercise is highly effective in preventing and treating a wide range of chronic progressive and age-related diseases, including musculoskeletal, metabolic, and cardiovascular disorders.^{15, 16} Furthermore, regular exercise is crucial in the context of neurodegenerative diseases, as it helps both to reduce the risk of their onset and slow their progression.¹⁶ Eftestol et al.¹⁷ recently demonstrated that juvenile climbing exercises in adult rats result in the development of a muscle memory, which effectively enhances the effects of adult exercise. The authors propose that a lasting increase in the number of myonuclei may serve as the functional substrate for muscle memory, as observed in their recent studies and in other species and settings. Walzik et al. propose, based on their latest results, the potential of exercise as NAD+-modifying lifestyle intervention, a mechanism by which exercise may act beneficially in the prevention of age-related disease.¹⁸ Lastly, the differences in exercise effects on young and elderly human probands studied by Frandsen et al. may hold potential for effectively adjusting exercise to avoid negative adaptive responses and maximize beneficial effects, especially for cardiovascular function.¹⁹

Genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction drive cellular aging and contribute to a decline in cellular function, and increased susceptibility to diseases associated with aging. Interesting recent research results pertaining to mechanism of aging include the decline of solute carrier function due to increasing oxidative stress,²⁰ differential aging-related effects on slow or fast myofibres,²¹ dysfunctions in lysosome-mitochondria interaction in the cardiovascular system²² and a decrease in proliferative capacity of radial stem cell astrocytes.²³ Circadian and sleep rhythm disruptions associated with advanced age and early-stage neurodegeneration show a certain overlap,²⁴ as do the characteristic histopathological changes found in pulmonary fibrosis and aging lungs,²⁵ potentially indicating shared underlying mechanisms.

The enduring relevance of the saying “we are as old as our arteries” remains, as cardiovascular disease (CVD) continues to dominate as the leading cause of death worldwide. The common underlying pathology of various CVDs is atherosclerosis, a chronic inflammatory condition characterized by abnormal lipid metabolism and arterial plaque formation, with endothelial dysfunction serving as a pivotal factor in its progression.²⁶ Endothelial function, which involves the health of the inner lining of blood vessels, is crucial for cardiovascular health and is known to deteriorate with age, contributing to the development of cardiovascular disease.²⁷ Improving endothelial function through lifestyle changes or medical treatments could therefore play a significant role in promoting healthy vascular aging.²⁸ Again exercise, recognized for its profound cardiovascular regeneration and benefits, plays a pivotal role in promoting endothelial function and cardiovascular health and protecting against CVDs, particularly through resistance training, which induces acute and chronic adaptations beneficial for metabolic and cardiorespiratory fitness.²⁹ Notably, individual shear rate therapy (ISRT), a non-invasive passive vascular exercise therapy, has shown promise in improving clinical outcomes for peripheral artery disease by harnessing increased shear forces to promote collateral growth without adverse effects, highlighting the potential of personalized precision medicine in combating CVDs.³⁰ ISRT significantly improves tolerability, safety, and effectiveness in patients with lower extremity atherosclerotic disease.³¹

Recent advances in aging research have expanded our understanding of the biological mechanisms underlying aging and age-related diseases. Breakthroughs in genetic and molecular biology have identified key pathways, such as cellular senescence, mitochondrial dysfunction, and epigenetic changes. Innovations like CRISPR and single-cell sequencing enable precise manipulation of these mechanisms, leading to potential therapeutic targets. Lifestyle interventions, including diet and exercise, have also shown their impact on longevity and healthspan. The field is rapidly progressing, with new discoveries offering promising ways to combat age-related diseases. Continued interdisciplinary research and technological advancements are crucial for translating these findings into clinical applications, ultimately improving the quality of life for the aging population.

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