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Changing Immunity Status in Geriatrics: Challenges and Clinical Relevance- A Narrative Review

Changing Immunity Status in Geriatrics: Challenges and Clinical Relevance- A Narrative Review

Dr. Vishnu Senthil, Dr. Mainak Roy

Abstract

Aging is associated with profound alterations in both innate and adaptive immunity, collectively termed immune senescence, which contribute to increased susceptibility to infections, impaired tissue repair, chronic inflammation, and reduced vaccine responsiveness. These changes have significant implications in geriatric orthopaedics, influencing fracture healing, implant integration, postoperative infection risk, and rehabilitation outcomes.

The innate immune system, including neutrophils, macrophages, dendritic cells, natural killer cells, and complement pathways, undergoes functional decline, while adaptive immunity shows reduced T-cell and B-cell diversity, impaired memory responses, and altered cytokine signaling. Chronic low-grade inflammation, or inflammaging, further exacerbates tissue damage and delays recovery. Strategies to counter immune-senescence encompass lifestyle interventions such as regular exercise, nutritional optimization including protein and micronutrient supplementation, vaccination, pharmacological agents such as senolytics and TLR agonists, and regenerative therapies like mesenchymal stem cells and exosomes. Integrating these approaches into clinical practice can enhance immune competence, accelerate healing, reduce postoperative complications, and improve functional outcomes in elderly patients. Future research should focus on personalized immunomodulatory strategies and translational therapies to optimize geriatric orthopaedic care.

Keywords

Geriatrics; Immunosenescence; Innate immunity; Adaptive immunity; Orthopaedics; Fracture healing; Regenerative therapy; Vaccination; Inflammaging; Elderly patients

Introduction

The World Health Organization estimates that by 2050 nearly 2.1 billion people will fall into age group > 60 yrs, representing over 20% of the global population, while in India alone the elderly population is projected to exceed 300 million, significantly impacting healthcare demands. Aging is accompanied by gradual decline in multiple physiological systems, including the immune system, a process known as immunosenescence. This age-related immune deterioration involves complex alterations in both innate and adaptive immunity, with some components becoming less responsive and others dysregulated.

In parallel, chronic low-grade systemic inflammation, termed inflammaging, contributes to the development of age-associated conditions such as atherosclerosis, type 2 diabetes, osteoporosis, neurodegenerative disorders, and frailty syndromes. The interplay between immunosenescence and inflammaging creates a paradox in which older adults are simultaneously vulnerable to infections while predisposed to chronic inflammatory diseases, a phenomenon starkly highlighted during the COVID-19 pandemic(1).

Clinically, the implications of altered immunity in the elderly span multiple specialties. Older adults face heightened susceptibility to bacterial pneumonia, urinary tract infections, sepsis, and viral reactivations, while reduced tumor immune surveillance increases cancer risk. In orthopaedics, immune dysregulation impairs wound healing, elevates the risk of prosthetic joint infections, and delays bone regeneration, complicating fracture recovery and rehabilitation.

Vaccine responses are similarly impaired, prompting the development of adjuvanted, high-dose, and recombinant formulations tailored for older populations, highlighting the need for adaptive public health strategies(2).

Beyond individual health, altered geriatric immunity carries significant societal and healthcare implications. Increased susceptibility to infections, chronic disease, and impaired recovery translates into higher healthcare utilization, costs, and caregiver burden, particularly in low- and middle-income countries with limited geriatric care infrastructure.

In orthopedic surgery, immune aging has direct consequences on postoperative outcomes, fracture healing, and prosthesis integration, emphasizing the necessity of integrating immunological considerations into perioperative planning. Addressing these challenges requires a multifaceted approach, including vaccination, nutritional optimization, regular exercise, pharmacologic interventions, and ongoing research into immune rejuvenation strategies. This review provides a detailed narrative on the cellular and molecular changes in aging immunity, the systemic effects of inflammaging, and the clinical implications across specialties, particularly orthopaedics, aiming to inform clinicians, researchers, and policymakers and ultimately translate scientific understanding into strategies that promote healthier aging, reduce morbidity, and enhance quality of life in the growing elderly population(3).

 

Innate Immunity and Aging

The innate immune system serves as the body’s first line of defense, providing rapid, non-specific protection against pathogens and tissue injury through physical barriers, cellular effectors, and soluble mediators. Unlike adaptive immunity, which requires prior antigen exposure to generate memory, innate immunity recognizes conserved pathogen-associated or damage-associated molecular patterns and responds within minutes to hours.

In elderly individuals, however, this frontline defense undergoes significant alterations, collectively termed innate immunosenescence. While cell numbers may remain relatively stable, functional competence declines, leading to increased susceptibility to infections, impaired tissue repair, and paradoxically heightened chronic low-grade inflammation. These changes are particularly relevant in orthopaedic practice, contributing to pneumonia, sepsis, poor wound healing, and perioperative complications(4).

The complement system is similarly dysregulated, combining impaired microbial clearance with enhanced chronic inflammation, while other innate-like lymphocytes, including γδ T-cells and mucosal-associated invariant T-cells, show functional decline, further compromising barrier immunity(6).

Clinically, these changes manifest as increased mortality from infections, delayed wound healing, higher surgical site and periprosthetic joint infection rates, impaired osseointegration of implants, and reduced tumor surveillance, which collectively complicate orthopaedic and general medical care in the elderly(7).

Adaptive Immunity and Aging

The adaptive immune system constitutes the highly specialized arm of host defense, providing antigen-specific recognition and long-term immunological memory. Unlike the innate system, which responds rapidly and nonspecifically, adaptive immunity tailors its response to distinct pathogens and retains memory for future encounters, primarily through T and B lymphocytes. With aging, this system undergoes profound functional decline, known as adaptive immunosenescence, characterized by reduced lymphocyte repertoire diversity, impaired clonal expansion, diminished vaccine responsiveness, and increased autoimmunity. These alterations contribute to heightened susceptibility to infections, malignancies, and delayed wound and fracture healing in older adults, making them clinically significant across medical and surgical specialties, including orthopaedics(8).

A central feature of adaptive immunosenescence is thymic involution, which begins in early adulthood and accelerates with age. These cells display diminished proliferative capacity and reduced cytotoxicity, limiting effective pathogen and tumor clearance and increasing the risk of chronic infections and malignancies, including those affecting bone and soft tissues(9).

Regulatory T cells (Tregs) show altered dynamics with aging; although their numbers may increase, their functional capacity is inconsistent, contributing both to autoimmunity and impaired pathogen defense. B-cell immunity is also compromised, with reduced naïve B-cell output, an accumulation of functionally impaired memory cells, and contraction of the immunoglobulin repertoire. Somatic hypermutation and class-switch recombination are less efficient, leading to antibodies with lower affinity and neutralizing capacity, which explains reduced vaccine efficacy and increased susceptibility to infections. Dysregulated B-cell tolerance also promotes autoantibody production, increasing the prevalence of autoimmune disorders in the elderly(10).

Adaptive immunity intersects closely with musculoskeletal health through osteoimmunology, as senescent T and B cells produce pro-inflammatory cytokines that promote osteoclast activation, bone resorption, and fragility fractures. Impaired adaptive responses delay bone repair and mineralization after trauma or surgery, underscoring why orthopaedic complications are more severe in older patients. Vaccination remains a cornerstone of preventive strategies, but diminished antigen presentation, lymphocyte proliferation, and memory generation limit efficacy, particularly against respiratory pathogens such as influenza, pneumococcus, and SARS-CoV-2. High-dose, adjuvanted, and booster vaccine strategies are being developed to overcome these limitations, with variable success(11).

Inflammaging and Chronic Low-Grade Inflammation

Inflammaging, a hallmark of immune aging, refers to the chronic, low-grade systemic inflammation that characterizes elderly physiology. Unlike acute inflammation, which is protective and resolves after infection or injury, inflammaging is persistent, often subclinical, and has widespread effects across organ systems.

It arises at the intersection of immunosenescence, metabolic dysregulation, and tissue degeneration, and is increasingly recognized as a central driver of age-related diseases, including atherosclerosis, type 2 diabetes, neurodegeneration, sarcopenia, osteoporosis, and impaired wound and fracture healing(12).

Autophagy and apoptosis further exacerbate the problem by allowing senescent cells and dysfunctional mitochondria to persist, releasing reactive oxygen species and mitochondrial DNA that perpetuate sterile inflammation(13).

Lifelong antigenic exposure also contributes to inflammaging. Chronic infections with latent viruses such as CMV, HSV, and EBV maintain continuous immune activation, driving clonal expansion of T cells that dominate the repertoire but exhibit functional exhaustion. This chronic immune stimulation depletes energetic reserves, weakens responses to new pathogens, and accelerates immunosenescence. These neurological impairments further complicate medical and surgical care in elderly patients(14).

In orthopaedic practice, persistent low-grade inflammation impairs angiogenesis, fibroblast activity, collagen deposition, and bone remodeling, resulting in delayed wound healing, higher rates of surgical site infections, nonunion, and malunion of fractures. Psychological consequences, including fatigue, depression, and cognitive decline, further reduce resilience in elderly patients(15).

Strategies to counter inflammaging focus on lifestyle, pharmacologic, and nutritional interventions. Regular exercise and caloric restriction reduce systemic inflammation, improve metabolic function, and enhance immune responsiveness. Pharmacological approaches such as IL-6 inhibitors, statins, and metformin are under investigation, while senolytics—drugs targeting senescent cells—show promise in decreasing pro-inflammatory burden. Nutritional supplementation with omega-3 fatty acids, polyphenols, and vitamin D may further modulate chronic inflammation and support healthier aging(14).

Clinical Implications of Immune Aging

The biological changes in both innate and adaptive immunity during aging do not remain confined to cellular or molecular pathways; rather, they manifest in a wide spectrum of clinical consequences that directly impact morbidity, mortality, and quality of life in the elderly. The impaired coordination between immune components, coupled with the phenomenon of inflammaging, translates into increased susceptibility to infections, reduced vaccine effectiveness, greater cancer incidence, altered autoimmune profiles, and delayed wound or fracture healing. These clinical implications form the practical dimension of immunosenescence and highlight the urgency of addressing immune health in geriatric populations(16).

Increased Susceptibility to Infections

One of the most prominent outcomes of immune aging is heightened vulnerability to infectious diseases. Elderly individuals are disproportionately affected by common community-acquired infections such as pneumonia, urinary tract infections, skin and soft tissue infections, and gastrointestinal infections.

Hospital-acquired infections, including those caused by multidrug-resistant organisms, are also more common in older adults due to prolonged hospital stays, frequent catheterization, and impaired immune defense(17).

Orthopedically, infection risk carries significant implications. Elderly patients undergoing joint replacement or fracture fixation surgeries face a substantially higher risk of surgical site infections and periprosthetic joint infections (PJI). Even with stringent aseptic precautions, impaired neutrophil activity, reduced complement function, and inadequate adaptive immune responses hinder bacterial clearance from surgical sites and prosthetic surfaces. Once infection sets in, biofilm formation further complicates eradication, leading to prolonged antibiotic courses, revision surgeries, and often loss of function(19).

Altered Autoimmune and Inflammatory Diseases

Paradoxically, while immune function declines with age, certain autoimmune phenomena become more prevalent in the elderly. This is partly explained by the expansion of autoreactive T-cell and B-cell clones due to thymic involution and reduced tolerance mechanisms. Diseases such as rheumatoid arthritis, giant cell arteritis, and polymyalgia rheumatica are more common in older populations and are sustained by chronic low-grade inflammation. The presentation of autoimmune conditions in the elderly may differ from younger patients, often being more subtle, atypical, or overlapping with age-related degenerative processes, complicating diagnosis and management(24).

In orthopedic practice, autoimmune conditions carry additional importance. For instance, rheumatoid arthritis in elderly patients is frequently complicated by osteoporosis and increased fracture risk, while long-term use of corticosteroids further weakens bone integrity. Similarly, autoimmune-driven inflammation can impair joint function, necessitating surgical interventions such as arthroplasty, which themselves are complicated by immunosenescence-related infection risks(25).

Delayed Wound and Fracture Healing

Another significant implication of immune aging is impaired tissue repair. Normal wound and fracture healing requires a finely orchestrated sequence of inflammatory, proliferative, and remodeling phases, each heavily dependent on immune–tissue interactions. In the elderly, neutrophil and macrophage dysfunction delays the resolution of inflammation, while impaired angiogenesis, fibroblast migration, and collagen synthesis slow down the proliferative phase. Chronic inflammation further disrupts tissue remodeling, leading to fragile scars, chronic wounds, and nonunion fractures(26).

Sepsis and Dysregulated Inflammatory Responses

Elderly patients not only have increased susceptibility to infections but also exhibit an exaggerated systemic inflammatory response once infection becomes systemic. Sepsis in older adults is characterized by a paradoxical combination of hyperinflammation (cytokine storm) and immunoparalysis (inability to clear pathogens effectively). This dysregulation explains the high mortality rates from sepsis in the elderly despite aggressive treatment. Importantly, clinical signs of infection such as fever or leukocytosis are often muted in this population, leading to diagnostic delays and worse outcomes(28).

Frailty, Sarcopenia, and Reduced Resilience

The cumulative impact of immune aging contributes to frailty, a multidimensional syndrome characterized by reduced physiological reserve and increased vulnerability to stressors. Sarcopenia, driven by chronic inflammation and impaired anabolic signaling, further reduces resilience to illness, surgery, or trauma. Frail elderly patients are more likely to experience postoperative complications, slower rehabilitation, and poorer functional recovery after orthopaedic interventions. Thus, immune aging is tightly intertwined with the geriatric syndrome of frailty, emphasizing the need for holistic care that integrates immunological, nutritional, and rehabilitative strategies(29).

Orthopedic Relevance of Immunosenescence

Orthopedic practice is uniquely influenced by the aging immune system because successful outcomes in bone and joint surgery, trauma care, and rehabilitation depend not only on surgical skill but also on biological processes such as wound healing, bone regeneration, and infection control—all of which are deeply interwoven with immune competence.

As the global population ages, orthopaedic surgeons increasingly encounter elderly patients presenting with fractures, degenerative joint disease, osteoporosis, malignancy-related skeletal complications, and post-traumatic conditions.

In these individuals, immunosenescence and inflammaging significantly modify disease progression, surgical risk, and postoperative recovery. Recognizing and addressing these immune-related challenges has therefore become a cornerstone of modern geriatric orthopaedics(30).

Fracture Healing and Bone Regeneration

Fracture healing is a complex, multistage biological process that relies heavily on immune–bone interactions. The early inflammatory phase of fracture repair is orchestrated by neutrophils and macrophages, which not only clear necrotic debris but also release cytokines and growth factors that recruit mesenchymal stem cells (MSCs) to the fracture site. These MSCs subsequently differentiate into osteoblasts and chondrocytes, initiating callus formation and eventual bone remodeling. In the elderly, innate immune dysfunction significantly impairs this early phase. Neutrophils in older adults display reduced chemotaxis and phagocytosis, leading to prolonged persistence of necrotic tissue and delayed transition from inflammation to repair. Likewise, macrophages show impaired polarization from pro-inflammatory M1 to reparative M2 phenotypes, resulting in inadequate recruitment of osteoprogenitors and poor angiogenic signaling(31).

As a consequence, elderly patients often exhibit delayed fracture union or outright nonunion. Clinical studies consistently demonstrate that age is a strong independent predictor of poor bone healing outcomes, even after accounting for comorbidities such as diabetes or osteoporosis. Moreover, inflammaging contributes to chronic elevation of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which inhibit osteoblast differentiation while promoting osteoclastogenesis. This cytokine imbalance tilts the bone remodeling equilibrium towards resorption, further impairing structural recovery after fracture(32).

Implant Osseointegration and Prosthetic Success

Joint replacement surgery has become one of the most transformative interventions in orthopaedics, offering elderly patients with osteoarthritis or fracture sequelae a chance at restored mobility and pain relief. However, successful arthroplasty relies on effective osseointegration, the process by which bone grows into and stabilizes an implant surface. Immunosenescence directly compromises this critical biological process(33).

At the cellular level, macrophages and dendritic cells regulate the early host response to implant materials. In younger individuals, a balanced immune reaction promotes angiogenesis, osteoblast recruitment, and stable bone–implant contact. In older adults, impaired macrophage function, coupled with dysregulated cytokine release, often leads to a prolonged inflammatory response that hinders osteoblastic activity and angiogenesis. Furthermore, chronic low-grade inflammation associated with inflammaging predisposes elderly patients to fibrous encapsulation of implants rather than osseointegration, thereby increasing the risk of aseptic loosening over time(34).

Another dimension is the reduced regenerative potential of MSCs in older adults, compounded by impaired immune–stromal communication. This reduces the capacity for bone ingrowth around prosthetic surfaces. Clinically, this manifests as higher rates of implant failure and the need for revision surgeries, which themselves are associated with increased morbidity and mortality in the elderly(35).

Osteoporosis and Immune Aging

Osteoporosis, one of the most prevalent conditions in geriatric orthopaedics, is intimately linked to immune aging. Beyond the well-known hormonal influences, there is growing recognition that immune dysregulation contributes to bone loss—a field now referred to as osteoimmunology. Chronic low-grade inflammation driven by inflammaging increases osteoclast activity through cytokines such as IL-6 and TNF-α, leading to accelerated bone resorption. Simultaneously, impaired osteoblast function due to macrophage and T-cell dysfunction reduces new bone formation(36).

This dual mechanism accelerates the loss of bone mass and quality, predisposing elderly patients to fragility fractures. Such fractures, particularly of the hip and vertebrae, carry devastating consequences including loss of independence, institutionalization, and high one-year mortality rates. Thus, osteoporosis is not merely a skeletal disease but a systemic manifestation of immune aging. For orthopaedic surgeons, this highlights the importance of integrating bone health optimization into routine geriatric care, including pharmacological interventions such as bisphosphonates, denosumab, or anabolic agents, alongside lifestyle measures that also modulate immune function(37).

Rehabilitation and Recovery After Orthopaedic Interventions

Successful recovery after orthopaedic surgery or fracture repair extends beyond the operating theatre, relying on effective rehabilitation. Here too, immune aging plays a crucial role. Chronic inflammation promotes sarcopenia, the loss of muscle mass and function, which directly impairs mobility and rehabilitation outcomes. Frailty, driven partly by immune dysregulation, reduces physiological reserve and makes elderly patients less able to tolerate rehabilitation protocols. Furthermore, impaired vaccine responses and susceptibility to infections may prolong hospital stays, delay mobilization, and increase the risk of complications such as pressure ulcers or deep vein thrombosis(38).

Addressing these challenges requires a multidisciplinary approach. Nutritional support, physiotherapy tailored to frail patients, and early mobilization strategies must be combined with careful immune optimization to achieve the best possible functional outcomes. For orthopaedic surgeons, awareness of these immunological constraints enables realistic counseling of patients and families regarding recovery trajectories and expected outcomes(39).

Strategies to Counter Immunosenescence

Counteracting immunosenescence is essential to enhance infection resistance, tissue repair, and overall recovery in elderly patients, particularly in orthopaedic care.

Lifestyle interventions, especially regular aerobic and resistance exercise, play a vital role in maintaining immune competence. Prehabilitation programs that combine strength training, balance exercises, and mobility routines have shown to accelerate postoperative recovery, improve functional outcomes, and reduce complications in older orthopaedic patients(40).

Nutritional optimization is equally critical. Adequate protein intake provides the building blocks for immune cells and supports collagen synthesis necessary for bone and wound healing. Micronutrients such as zinc, selenium, and vitamins C and D are indispensable for maintaining innate and adaptive immune responses, enhancing neutrophil function, and promoting T-cell proliferation. Omega-3 fatty acids contribute to the resolution of inflammation, supporting tissue repair and mitigating systemic inflammaging. Optimizing nutrition preoperatively in elderly orthopaedic patients can reduce infection rates, improve fracture healing, and support rehabilitation outcomes(41).

Vaccination remains a cornerstone for infection prevention in geriatric populations. Although immune responses are generally weaker in older adults due to impaired dendritic cell function and reduced T-cell activity, high-dose or adjuvanted vaccines can improve efficacy. Preoperative immunization against influenza, pneumococcus, and shingles can reduce postoperative complications, hospitalizations, and morbidity associated with infections(42).

Pharmacological and immunomodulatory strategies are emerging as promising interventions. Senolytic drugs, which selectively eliminate senescent immune cells, can reduce chronic inflammation and enhance tissue repair. Toll-like receptor agonists and small molecules targeting metabolic pathways, such as mTOR inhibitors, may rejuvenate immune function, improve pathogen recognition, and restore inflammatory balance. Anti-cytokine therapies targeting IL-6 or TNF-α may further reduce harmful systemic inflammation without compromising host defense(43).

Regenerative approaches, including mesenchymal stem cell therapy and exosome-based interventions, offer innovative strategies to restore immune competence and promote tissue regeneration. MSCs enhance macrophage M2 polarization, secrete anti-inflammatory cytokines, and support osteogenesis and angiogenesis. Exosomes deliver bioactive molecules capable of rejuvenating senescent immune cells and promoting fracture healing, particularly in elderly patients with delayed union or impaired bone regeneration(44).

A multimodal approach, integrating exercise, nutrition, vaccination, pharmacological agents, and regenerative therapies, is likely the most effective strategy to counter immunosenescence. Tailoring interventions based on individual immune profiles, frailty status, and comorbidities can optimize outcomes, reduce complications, and enhance resilience in geriatric orthopaedic patients(45).

Conclusion

Aging alters both innate and adaptive immunity, increasing infection risk, delaying tissue repair, and complicating orthopaedic outcomes such as fracture healing and implant integration. Immunosenescence and chronic low-grade inflammation contribute to higher infection rates, delayed union, and reduced recovery after trauma or surgery. Proactive measures—including nutrition, exercise, vaccination, and targeted therapies—along with personalized strategies like immune profiling and prehabilitation, can improve resilience and outcomes. While declining immunity remains a challenge, applying insights from immunosenescence research and advancing immunomodulatory or regenerative therapies holds promise for enhancing healing, recovery, and quality of life in elderly patients.

References

  • Noto S. Perspectives on Aging and Quality of Life. Healthcare. 2023 Jul 26;11(15):2131.
  • Theodorakis N, Feretzakis G, Hitas C, Kreouzi M, Kalantzi S, Spyridaki A, et al. Immunosenescence: How Aging Increases Susceptibility to Bacterial Infections and Virulence Factors. Microorganisms. 2024 Oct;12(10):2052.
  • Atella V, Piano Mortari A, Kopinska J, Belotti F, Lapi F, Cricelli C, et al. Trends in age‐related disease burden and healthcare utilization. Aging Cell. 2019 Feb;18(1):e12861.
  • Aristizábal B, González Á. Innate immune system. In: Autoimmunity: From Bench to Bedside [Internet]. El Rosario University Press; 2013 [cited 2025 Sep 29]. Available from:
    https://www.ncbi.nlm.nih.gov/books/NBK459455/
  • Colaço HG, Moita LF. Initiation of innate immune responses by surveillance of homeostasis perturbations. FEBS J. 2016;283(13):2448–57.
  • Zhang J, Shao Y, Wu J, Zhang J, Xiong X, Mao J, et al. Dysregulation of neutrophil in sepsis: recent insights and advances. Cell Commun Signal. 2025 Feb 14;23(1):87.
  • López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023 Jan 19;186(2):243–78.
  • In brief: The innate and adaptive immune systems. In: InformedHealth.org [Internet]. Institute for Quality and Efficiency in Health Care (IQWiG); 2023 [cited 2025 Sep 29]. Available from:
    https://www.ncbi.nlm.nih.gov/books/NBK279396/
  • Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. The Adaptive Immune System. In: Molecular Biology of the Cell 4th edition [Internet]. Garland Science; 2002 [cited 2025 Sep 29]. Available from:
    https://www.ncbi.nlm.nih.gov/books/NBK21070/
  • Wang R, Lan C, Benlagha K, Camara NOS, Miller H, Kubo M, et al. The interaction of innate immune and adaptive immune system. MedComm. 2024;5(10):e714.
  • Zupan J, Jeras M, Marc J. Osteoimmunology and the influence of pro-inflammatory cytokines on osteoclasts. Biochem Medica. 2013 Feb 15;23(1):43–63.
  • Saavedra D, Añé-Kourí AL, Barzilai N, Caruso C, Cho KH, Fontana L, et al. Aging and chronic inflammation: highlights from a multidisciplinary workshop. Immun Ageing A. 2023 Jun 8;20:25.
  • Inflammaging – an overview | ScienceDirect Topics [Internet]. [cited 2025 Sep 29]. Available from:
    https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/inflammaging
  • Li X, Li C, Zhang W, Wang Y, Qian P, Huang H. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther. 2023 Jun 8;8(1):239.
  • Fulop T, Larbi A, Pawelec G, Khalil A, Cohen AA, Hirokawa K, et al. Immunology of Aging: the Birth of Inflammaging. Clin Rev Allergy Immunol. 2023;64(2):109–22.
  • Ponnappan S, Ponnappan U. Aging and Immune Function: Molecular Mechanisms to Interventions. Antioxid Redox Signal. 2011 Apr 15;14(8):1551–85.
  • Quiros-Roldan E, Sottini A, Natali PG, Imberti L. The Impact of Immune System Aging on Infectious Diseases. Microorganisms. 2024 Apr 11;12(4):775.
  • Ginaldi L, Loreto MF, Corsi MP, Modesti M, De Martinis M. Immunosenescence and infectious diseases. Microbes Infect. 2001 Aug 1;3(10):851–7.
  • Immune aging and infectious diseases | Chinese Medical Journal [Internet]. [cited 2025 Sep 29]. Available from:
    https://mednexus.org/doi/10.1097/CM9.0000000000003410
  • Lord JM. The effect of aging of the immune system on vaccination responses. Hum Vaccines Immunother. 2013 Jun 1;9(6):1364–7.
  • Doherty TM, Weinberger B, Didierlaurent A, Lambert PH. Age-related changes in the immune system and challenges for the development of age-specific vaccines. Ann Med. 2025 Dec;57(1):2477300.
  • Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest. 2007 May 1;117(5):1137–46.
  • Montégut L, López-Otín C, Kroemer G. Aging and cancer. Mol Cancer. 2024 May 18;23(1):106.
  • Weyand CM, Shao L, Goronzy JJ. Immune Aging and Rheumatoid Arthritis. Rheum Dis Clin North Am. 2010 May;36(2):297–310.
  • Fülöp T, Larbi A, Dupuis G, Pawelec G. Ageing, autoimmunity and arthritis: Perturbations of TCR signal transduction pathways with ageing – a biochemical paradigm for the ageing immune system. Arthritis Res Ther. 2003;5(6):290–302.
  • Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: Mechanisms, signaling, and translation. Sci Transl Med. 2014 Dec 3;6(265):265sr6.
  • Shema C, Lu Y, Wang L, Zhang Y. Monocyte alteration in elderly hip fracture healing: monocyte promising role in bone regeneration. Immun Ageing. 2024 Feb 3;21(1):12.
  • Ramoni D, Tirandi A, Montecucco F, Liberale L. Sepsis in elderly patients: the role of neutrophils in pathophysiology and therapy. Intern Emerg Med. 2024 Jun 1;19(4):901–17.
  • Wilson D, Jackson T, Sapey E, Lord JM. Frailty and sarcopenia: The potential role of an aged immune system. Ageing Res Rev. 2017 Jul;36:1–10.
  • Gheno R, Cepparo JM, Rosca CE, Cotten A. Musculoskeletal Disorders in the Elderly. J Clin Imaging Sci. 2012 Jul 28;2:39.
  • Rodrigues LP, Teixeira VR, Alencar-Silva T, Simonassi-Paiva B, Pereira RW, Pogue R, et al. Hallmarks of aging and immunosenescence: Connecting the dots. Cytokine Growth Factor Rev. 2021 Jun 1;59:9–21.
  • Taormina DP, Shulman BS, Karia R, Spitzer AB, Konda SR, Egol KA. Older Age Does Not Affect Healing Time and Functional Outcomes After Fracture Nonunion Surgery. Geriatr Orthop Surg Rehabil. 2014 Sep;5(3):116–21.
  • Hodges NA, Sussman EM, Stegemann JP. Aseptic and septic prosthetic joint loosening: Impact of biomaterial wear on immune cell function, inflammation, and infection. Biomaterials. 2021 Nov 1;278:121127.
  • Apostu D, Lucaciu O, Berce C, Lucaciu D, Cosma D. Current methods of preventing aseptic loosening and improving osseointegration of titanium implants in cementless total hip arthroplasty: a review. J Int Med Res. 2018 Jun;46(6):2104–19.
  • Zupan J, Strazar K, Kocijan R, Nau T, Grillari J, Marolt Presen D. Age-related alterations and senescence of mesenchymal stromal cells: Implications for regenerative treatments of bones and joints. Mech Ageing Dev. 2021 Sep 1;198:111539.
  • Patel D, Saxena B. Decoding osteoporosis: Understanding the disease, exploring current and new therapies and emerging targets. J Orthop Rep. 2025 Dec 1;4(4):100472.
  • Immunoporosis: The hidden link between aging immune cells and bone fragility – ScienceDirect [Internet]. [cited 2025 Sep 29]. Available from:
    https://www.sciencedirect.com/science/article/pii/S2214031X25001081
  • Larsson L, Degens H, Li M, Salviati L, Lee Y il, Thompson W, et al. Sarcopenia: Aging-Related Loss of Muscle Mass and Function. Physiol Rev. 2019 Jan 1;99(1):427–511.
  • Al-Dahan T, Murhekar S, Abed M, Shinde K. Understanding Barriers to Early Rehabilitation Following the Surgery for Fragility Hip Fractures: A Single-Centre Audit. Cureus. 2024 Oct;16(10):e71827.
  • Hieber C, Grabbe S, Bros M. Counteracting Immunosenescence-Which Therapeutic Strategies Are Promising? Biomolecules. 2023 Jul 6;13(7):1085.
  • Fu Y, Wang B, Alu A, Hong W, Lei H, He X, et al. Immunosenescence: signaling pathways, diseases and therapeutic targets. Signal Transduct Target Ther. 2025 Aug 6;10(1):250.
  • Villar-Álvarez F, de la Rosa-Carrillo D, Fariñas-Guerrero F, Jiménez-Ruiz CA. Immunosenescence, Immune Fitness and Vaccination Schedule in the Adult Respiratory Patient. Open Respir Arch. 2022 Jul 1;4(3):100181.
  • Frontiers | New Approaches to Combat Immunosenescence and Inflammaging: Mechanisms and Therapies [Internet]. [cited 2025 Sep 29]. Available from:
    https://www.frontiersin.org/research-topics/69767/new-approaches-to-combat-immunosenescence-and-inflammaging-mechanisms-and-therapies
  • Han X, Liao R, Li X, Zhang C, Huo S, Qin L, et al. Mesenchymal stem cells in treating human diseases: molecular mechanisms and clinical studies. Signal Transduct Target Ther. 2025 Aug 22;10:262.
  • Aiello A, Farzaneh F, Candore G, Caruso C, Davinelli S, Gambino CM, et al. Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention. Front Immunol [Internet]. 2019 Sep 25 [cited 2025 Sep 29];10. Available from:
    https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02247/full