JSUR Journal

Introduction

Aging is a complex biological process marked by progressive molecular and cellular damage, leading to the gradual deterioration of structure and function across multiple body systems. At the cellular level, this process is characterized by genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis-mechanisms now collectively defined as the “Hallmarks of Aging” [1]. Although aging impacts all organs and tissues, the most prominent changes are observed in systems responsible for mobility (musculoskeletal), cognition (neurological), and appearance (integumentary and connective tissue). These changes often arise from shared pathological mechanisms, such as chronic inflammation and stem cell exhaustion, which are increasingly recognized as fundamental drivers of multi-system decline [1-3] In recent years, anti-aging research has shifted from a primarily cosmetic focus toward a broader paradigm of systemic rejuvenation, acknowledging that interventions targeting a single system often confer pleiotropic benefits across others [4]. For instance, senolytic therapies not only eliminate senescent cells in the skin but also enhance vascular function and promote muscle regeneration [5]. Likewise, exercise-traditionally valued for maintaining muscle mass-has been shown to stimulate neurogenesis and improve bone density, primarily through myokine-mediated signaling pathways [6’7] . This interconnectedness highlights the importance of adopting a multi-system approach in modern anti-aging strategies. Understanding mechanisms of crosstalk-such as how osteocalcin from bone influences brain function or how adipose tissue senescence accelerates vascular stiffening-is essential for developing comprehensive interventions. Emerging frameworks, such as 'geroscience,' now focus on targeting fundamental aging processes to delay the onset of multiple age-related conditions simultaneously [1,3]. This mini-review explores the pathophysiology of aging across seven key systems-bone, fat, muscle, neurological, vascular, connective tissue, and skin-examining both established and emerging rejuvenation strategies. (Figure 1; Table 1) It highlights how combinatorial approaches may act synergistically to counteract cross-system decline, while also addressing current translational challenges such as the optimization of personalized treatment protocols.

Figure 1: Multi-system aging.

Table 1: Aging pathologies and treatment by system.

Aging Pathology and Anti-aging Treatment Strategies for Different Systems

Bone System

Aging Pathology: Bone aging is characterized by the accelerated loss of mineral density and trabecular thinning, along with cortical porosity, leading to osteoporosis and fragility fractures [8-10]. A deficiency in dietary calcium triggers a significant increase in RANKL production, particularly in osteocytes, which become the primary drivers of subsequent bone loss [11]. As individuals age, the balance between bone resorption and formation shifts, resulting in increased bone loss, often exacerbated by hormonal changes, particularly in postmenopausal women. Postmenopausal women experience trabecular bone loss due to estrogen withdrawal, which enhances osteoclastogenesis through NF-κB signaling [12]. Regarding facial bone aging, bone resorption, especially in the maxillary and mandibular regions, plays a critical role. This leads to midface retrusion, deepening of the nasolabial folds, and overall facial sagging [13].

Treatment Strategies

• Bone Regeneration Therapies: [14] Techniques such as bone grafting, mesenchymal stem cell therapy, and the application of Bone Morphogenetic Proteins (BMPs) are being investigated for their potential to promote bone growth and repair.
• Pharmacological Interventions: [15] Medications like bisphosphonates and Selective Estrogen Receptor Modulators (SERMs) help reduce bone loss by inhibiting resorption.
• Calcium Hydroxylapatite (CaHA) Injections: [16] These injections are used for periosteal filling, aiding in the restoration of skeletal support.
• Low-Intensity Pulsed Ultrasound (LIPUS): [17] This therapy stimulates bone metabolism and helps delay bone resorption.
• Bioactive Glass Therapy: [18] This therapy releases calcium and phosphate ions, promoting bone regeneration.

Fat System

Aging Pathology: With age, body fat undergoes redistribution, characterized by a decrease in subcutaneous fat and an increase in visceral fat. This shift in fat distribution can lead to changes in body shape, such as the loss of facial volume and the accumulation of fat around internal organs, which increases the risk of metabolic disorders [19]. In terms of facial fat aging, age-related fat compartmentalization results in the loss of deep fat (e.g., SOOF) and the descent of superficial fat, causing an imbalanced facial appearance [20]. Consequently, deep fat atrophy contributes to midface hollowing, while the herniation of superficial fat worsens nasolabial fold prominence [20].

Treatment Strategies

• Adipose-Derived Stem Cells: [21] These cells show promise for regeneration and fat tissue restoration, providing a potential approach for restoring facial volume and reducing visceral fat.
• Fat Repositioning Techniques: [22] Cosmetic procedures such as fat grafting have gained popularity for facial rejuvenation and restoring lost volume in aging individuals.
• Poly-L-Lactic Acid (PLLA) Micro-Spheres: [23] These stimulate collagen production while enhancing the retention of fat grafts.
• Radiofrequency Microneedling (RF-MN): [24] This technique improves skin texture by promoting vascularization and remodeling of adipocytes.

Muscle System

Aging Pathology: Muscle mass and strength decline with age, a condition known as sarcopenia, which leads to functional impairments, frailty, and an increased risk of falls. Sarcopenia is influenced by factors such as reduced protein synthesis, hormonal changes, and physical inactivity [25]. In terms of facial muscle aging, it involves both muscle atrophy and compensatory hyperactivity, resulting in the development of both static and dynamic wrinkles [26]. Additionally, the decline of fast-twitch muscle fibers (e.g., zygomaticus major) with age weakens smile dynamics [27]. Electromyography (EMG) reveals increased involuntary contractions in hypertrophied facial muscles [28].

Treatment Strategies

• Exercise and Nutrition: [29] Resistance training combined with adequate protein intake has been shown to counteract muscle loss and improve strength in aging individuals.
• Regenerative Medicine: [30] The use of satellite cells, myostatin inhibitors, and stem cell therapies is being explored as potential treatments to restore muscle mass and function.
• Targeted Botulinum Toxin (BoNT) Injection: [31] EMG-guided micro-dosing allows for selective muscle relaxation without the risk of over-paralysis.
• Myomodulation with Fillers: [32] Restoring volume can enhance muscle tonicity.
• Microcurrent Stimulation (NuFACE): [33] A randomized trial demonstrated an 18% improvement in muscle tone with this treatment.

Neurological System

Aging Pathology: Aging affects the neurological system through the gradual decline in cognitive functions, including memory, attention, and processing speed. Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are common among older adults, influenced by a combination of genetic, environmental, and lifestyle factors [34]. Age-related neurodegeneration also impacts facial nerve function, impairing skin barrier efficiency and collagen synthesis. The emerging "Neuro-Skin Axis" theory emphasizes the connection between neural pathways and skin health. [35]. Imaging studies show a direct correlation between nerve compression and facial muscle spasticity [36]. With age, axonal density and nerve regeneration capabilities decline, impacting facial expressions and symmetry [37].

Treatment Strategies:

• Cognitive Training and Neuroplasticity: [38] Mental exercises, coupled with cognitive training, aim to enhance brain function and neuroplasticity, thereby promoting cognitive health.
• Pharmacological Interventions: [39] Neuroprotective drugs, such as cholinesterase inhibitors and antioxidants, are being used to slow the progression of neurological decline.
• Exosome Therapy: [40] Exosomes enriched with miR-21 support nerve axon regeneration.
• Fullerenes as Antioxidants: [41] These compounds reduce oxidative stress in nerve endings, enhancing neurotransmission.
• Magnetic Stimulation (TMS): [42] This technique improves neuromuscular coordination and facial expressiveness.

Vascular and Lymphatic Systems

Aging Pathology: Aging results in endothelial dysfunction, arterial stiffening, and an increased risk of cardiovascular diseases such as atherosclerosis and hypertension. These vascular changes contribute to reduced oxygen delivery to tissues, heightening the risk of stroke and heart attack [43]. In terms of facial vascular and lymphatic aging, a decrease in microvascular density leads to a dull skin tone, slower tissue repair, and the accumulation of metabolic waste. The age-related decline in capillary function is further compounded by reduced lymphatic flow, which exacerbates puffiness and inflammation [44].

Treatment Strategies

• Lifestyle Modifications: [45] Regular physical activity, a healthy diet, and smoking cessation are crucial for maintaining vascular health.
• Targeted Therapies: [46] Interventions such as endothelial progenitor cell therapy and the use of vasodilators are being explored to improve vascular health in aging individuals.
• Platelet-Rich Plasma (PRP) Injections: [47] The high VEGF content in PRP promotes angiogenesis and epidermal thickening.
• Low-Level Light Therapy (LLLT): [48] 633nm red light enhances blood flow and endothelial function.
• Nicotinamide Mononucleotide (NMN) Supplementation: [49] This supplementation boosts NAD+ levels, improving endothelial cell function.
• Pulsed Vacuum Drainage: [50] This technique enhances lymphatic circulation, helping to reduce edema.

Connective Tissue System

Aging Pathology: Connective tissues, including ligaments, tendons, and cartilage, undergo degeneration with age, resulting in joint pain, stiffness, and reduced mobility. Collagen production declines, and existing collagen fibers lose their elasticity, which contributes to the physical appearance of aging skin and joints [51]. In the face, the Superficial Musculoaponeurotic System (SMAS) and ligamentous structures are vital for maintaining facial contours. Aging leads to reduced elasticity and progressive sagging, with the SMAS layer losing elastin at a faster rate than the dermis. Ligamentous aging contributes to midface sagging [52].

Treatment Strategies

• Biostimulators: [53,54] Injectable biostimulators, such as AestheFill, stimulate collagen synthesis, enhancing skin texture and elasticity.
• Regenerative Therapies: [47] Stem cell injections and platelet-rich plasma (PRP) treatments show promise in promoting the healing and regeneration of connective tissues.
• Polydioxanone (PDO) Thread Lifting: [55] This technique provides structural support while stimulating collagen synthesis.
• High-Intensity Focused Ultrasound (HIFU): [56] MRI studies have shown improvements in skin tightness following HIFU treatment.

Skin System

Aging Pathology: The skin is one of the most visible indicators of aging, showing changes such as wrinkles, loss of elasticity, and pigmentation irregularities. As the skin loses collagen and elastin over time, it becomes more prone to sagging, thinning, and the formation of fine lines. Aging also impairs keratinocyte turnover and the integrity of the lipid barrier, leading to dryness, rough texture, and heightened sensitivity. As epidermal turnover slows with age, skin regeneration decreases. Additionally, transepidermal water loss increases, contributing to dehydration and irritation [57,58].

Treatment Strategies

• Topical Treatments: [59] Retinoids, antioxidants, and peptides are commonly included in skincare products to promote skin rejuvenation.
• Injectable Fillers and Biostimulators: [60] Hyaluronic acid fillers and biostimulators help restore volume, smooth wrinkles, and stimulate collagen production.
• Regenerative Medicine: [47] Stem cell-based treatments and PRP have shown promise in rejuvenating aging skin by promoting cell regeneration and collagen synthesis.
• Retinoid Microinfusion: [61] Microneedle-assisted delivery enhances the penetration of vitamin A.
• Biomimetic Lipids: [62] Ceramide-based formulations improve moisture retention in the skin.
• Microbiome Regulation: [63] Phage-based skincare selectively targets pathogenic bacteria while preserving beneficial skin flora.

Future Perspectives in Anti-Aging Research

As research into aging and anti-aging interventions advances, the field is shifting toward a more integrated, multi-system approach. Instead of focusing solely on one aspect of aging, emerging therapies are exploring the potential to rejuvenate multiple systems simultaneously. The future of anti-aging research is set to combine regenerative medicine, genetic interventions, and personalized therapies to address the complexities of aging in a more holistic manner. Several key areas for future research include:

• Regenerative Medicine: [14,21,47] Stem cell-based therapies, gene editing, and tissue engineering are among the most promising fields in anti-aging research. By targeting the cellular and molecular mechanisms underlying aging, these therapies could provide a more effective approach to rejuvenation.
• Longevity Science: [1,5] Researchers are increasingly investigating pathways associated with longevity, such as the roles of telomeres, cellular senescence, and autophagy in aging. Understanding and manipulating these processes could offer new opportunities for slowing or even reversing the aging process.
• Personalized Anti-Aging Therapies: [1,34] As we gain a deeper understanding of the genetic, epigenetic, and environmental factors influencing aging, personalized medicine will play a crucial role. Tailored therapies based on individual genetic profiles and lifestyle factors will optimize anti-aging treatments and improve outcomes.

Conclusion

The aging process affects multiple systems within the human body, each requiring distinct yet often interconnected strategies for rejuvenation. From bone density and muscle health to skin rejuvenation and neurological preservation, aging touches all aspects of our physiology. Advancements in anti-aging therapies, such as regenerative medicine, biostimulators, and personalized treatments, are offering promising solutions for healthier aging across these systems. Emerging research into longevity science and the role of cellular mechanisms, such as telomeres, senescence, and autophagy, holds the potential to slow or even reverse certain aspects of aging. By adopting a multi-system, holistic approach, the future of anti-aging medicine is poised to provide more comprehensive and effective interventions, optimizing not only the quality of life but also the longevity of individuals. As science continues to evolve, the integration of genetic, epigenetic, and environmental factors will further refine personalized therapies, enabling us to address the complexities of aging more effectively. Ultimately, these innovations pave the way for a future where aging is not simply endured but actively managed and improved.

Financial Disclosure Statement: No funding was received for this article.

Conflicts of interest: The authors declare no conflicts of interest.

Short Running Head (no more than 40 characters in length): Aging and anti-aging interventions

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