Rapamycin has been shown to extend lifespan and acts on pathologies underlying Alzheimer's disease and related dementias in animal models. However, rapamycin's clinical application remains underexplored.

We conducted a single-site open-label phase 1 clinical trial (ClinicalTrials.gov: NCT04200911) to examine the effects of rapamycin in humans. Eligible participants were people 55-85 years old with mild cognitive impairment or early-stage dementia, which was defined as having a Global Clinical Dementia Rating Scale Score of 0.5-1. All participants received rapamycin (1 mg/day) for eight weeks. The primary aim was to evaluate rapamycin's central nervous system penetrance by assaying drug levels in the cerebrospinal fluid (CSF) before and after treatment. Secondary aims evaluated safety, cognition, Alzheimer's disease, and inflammatory biomarkers in the CSF and plasma.

In ten participants (mean age 74 ± 4 years, 60% female), we find that rapamycin is not detectable in the CSF before or after treatment. After treatment, we find that twenty, mostly mild adverse events occur, systolic blood pressure and hemoglobin A1c increase, multiple erythrocyte parameters decrease, and there are no significant cognitive changes. Furthermore, we find that CSF phosphorylated tau-181 (mean change (95% confidence interval) pg/ml), 2.64 [0.70-4.59]), glial fibrillary acidic protein (6262.21 [3787.44-9373.84]), and neurofilament light (367.19 [204.28-561.61]) and plasma interferon gamma (4.37 [3.01-5.74]), interleukin 5 (0.33 [0.12-0.64]), vascular endothelial growth factor D (3741.03 [1505.98-5976.07]), soluble fms-like tyrosine kinase-1 (258.88 [89.03-428.74]) and placental growth factor (20.81 [12.38-29.25]) significantly increase (FDR-corrected p-value < 0.05).

Rapamycin is not detectable in the CSF before or after treatment, but several Alzheimer's disease and inflammatory biomarkers increase after treatment. Our results highlight the need to better understand the biological effects and clinical impact of repurposing rapamycin for Alzheimer's disease.

Enormous resources have been devoted to address the suboptimal response of tumor patients to immunotherapy. However, a crucial yet often overlooked factor in these effects is the strong correlation between the occurrence and development of tumors and the immune dysfunction associated with aging. Our study aims to rejuvenate aging T cells within tumor-draining lymph nodes (TdLNs) by using targeted delivery of rapamycin, a macrolide capable of mitigating aging-related decline in immune function, thereby enhancing the antitumor efficacy of immunotherapy in aged mice. The targeted delivery system relies on a bioorthogonal reaction that harnesses the click chemistry between the azide (N3) groups artificially introduced onto TdLNs and the dibenzocyclooctyne (DBCO) groups attached to the rapamycin-loaded micelles administered intradermally. Experimental data demonstrate that this approach has effectively restored the functionality of impaired CD8+ T cells in aged mice, thereby enhancing the antitumor response to immune checkpoint blockade (ICB) therapy to levels comparable to those in young mice. This study presents a promising strategy to combat the resistance to immunotherapeutic approaches commonly encountered among elderly tumor patients.

Metastatic outgrowth in distant microscopic niches requires sufficient nutrients, including fatty acids (FAs), to support tumor growth and to generate an immunosuppressive tumor microenvironment (TME). However, despite the important role of FAs in metastasis, the regulation of FA supply in metastatic niches has not been defined. In this report, we show that tumor endothelium actively promotes outgrowth and restricts antitumor cytolysis by transferring FAs into developing metastatic tumors. We describe a process of transendothelial FA delivery via endosomes that requires mTORC1 activity. Thus, endothelial cell-specific targeted deletion of Raptor (RptorECKO), a unique component of the mTORC1 complex, significantly reduced metastatic tumor burden that was associated with improved markers of T cell cytotoxicity. Low-dose everolimus that selectively inhibited endothelial mTORC1 improves immune checkpoint responses in metastatic disease models. This work reveals the importance of transendothelial nutrient delivery to the TME, highlighting a future target for therapeutic development.

The immune system has long been recognized for its critical role in the elimination of pathogens and the development of autoimmune diseases, but recent evidence demonstrates that it also contributes to noncommunicable diseases associated with biological aging processes, such as cancer, cardiovascular disease, neurodegeneration, and frailty. This review examines immunological biomarkers of aging, focusing on how the immune system evolves with age and its impact on health and disease. It discusses the historical development of immunological assessments, technological advancements, and the creation of novel biomarkers and models to study immune aging. We also explore the clinical implications of immune aging, such as increased susceptibility to infectious diseases, poor vaccine responses, and a higher incidence of noncommunicable diseases. In summary, we provide a comprehensive overview of current research, highlight the clinical relevance of immune aging, and identify gaps in knowledge that require further investigation.

Calorie restriction (CR) is a well known intervention associated with multifaceted anti-aging and pro-longevity health benefits. It induces complex physiological cellular and molecular adaptations, resulting in the fine-tuning of metabolic and immune responses in both homeostatic and diseased states. It has thus been extensively studied both preclinically and clinically, uncovering its therapeutic potential against inflammatory conditions, particularly autoimmune diseases. CR mimetics (CRMs), that is, molecules that mimic CR's effects, have also been widely investigated to counteract inflammatory states associated with numerous diseases, including autoimmunity. However, a comprehensive overview of how CR and CRMs modulate different aspects of immune responses, thereby potentially modifying autoimmunity, is still lacking. Here, we reviewed the latest progress on the impacts of CR and CRMs on the immune system and the current evidence on their potential translation in the clinical management of people with autoimmune diseases. First, we summarized different types of CR and CRMs and their main mechanisms of action. We next reviewed comprehensively how CR and CRMs modulate immune cells and discussed up-to-date preclinical and clinical advances in using CR and CRMs in the context of some of the most common autoimmune diseases. Finally, challenges faced in CR-related research and its translation into the clinic are discussed. SIGNIFICANCE STATEMENT: Calorie restriction (CR) encompasses various approaches for daily or intermittent reduction in calorie intake while maintaining adequate nutrient intake. It acts through cell-intrinsic and -extrinsic pathways to modulate immune cell functions. CR is emerging as a strategy for autoimmune disease management. CR's effects could be partially mimicked by molecules called CR mimetics, which are proposed to achieve CR's effects without reducing food intake. CR and CR mimetics have been tested as promising potential therapeutics in preclinical and clinical autoimmune disease studies.

Metabolic regulation plays a crucial role in extending the healthspan and lifespan across multiple organisms, including humans. Although numerous studies have identified the characteristics of the metabolome and potential biomarkers in long-lived populations worldwide, the metabolome landscape of Chinese centenarians remains largely unknown. This study characterised the plasma metabolic profiles of Chinese centenarians and nonagenarians and identified potential biomarkers of longevity.

A global untargeted metabolomics approach was used to analyze plasma samples from 65 centenarians (average age 101.72 ± 1.46 years), 53 nonagenarians (average age 98.92 ± 0.27 years), 47 older individuals (average age 64.66 ± 3.31 years), and 35 middle-aged participants (average age 33.91 ± 3.53 years) recruited from the Lishui region, an area of China well known for the longevity of its population.

The plasma metabolic profiles of centenarians and nonagenarians differed significantly from those of the two younger populations. Specifically, 211 and 114 differentially abundant metabolites (DAMs) were identified in the centenarian and nonagenarian groups, respectively. The majority of these DAMs were glycerophosphoethanolamines, glycerophosphocholines, fatty esters, fatty alcohols, fatty acyls, and fatty acids and conjugates. For example, the circulating levels of LysoPA (20:2), LysoPA (20:3), LysoPC (16:0), LysoPC (18:2), and LysoPE (20:4) were significantly lower in centenarians than in the older and middle-aged groups. A similar pattern was also observed in the nonagenarian population. Notably, the plasma levels of five DAMs - LysoPA (20:3), LysoPC (18:2), LysoPE (20:4), PG (18:0/18:1), and PG (18:1/18:2) - were significantly and continuously reduced with the ageing process. Pearson correlation analysis revealed that the reduced abundance of LysoPA (20:3), LysoPC (18:2), LysoPE (20:4), LysoPE (24:0), PG (18:0/18:1), and PG (18:1/18:2) was significantly and negatively associated with lifespan, from middle-age to centenarian. ROC analysis indicated that LysoPA (20:3), LysoPC (18:2), LysoPE (20:4), LysoPE (24:0), PG (18:0/18:1), and PG (18:1/18:2), as well as the combination of these six DAMs (AUC = 0.9074), had high predictive power for the human longevity phenotype.

This study elucidated the plasma metabolic landscape of centenarians and nonagenarians in China and identified several potential biomarkers for predicting human lifespan. Our findings will aid in understanding the metabolic regulation of longevity and may promote the clinical practice of gerontology in the future.

T cell aging contributes to the lower vaccine efficacy in older adults, yet the molecular mechanism remains elusive. Here, we show the density of initially responding naïve CD4+ T cells is instructive in T follicular helper (TFH) cell fate decisions and declines with age. A lower number of initially responding cells did not affect TFH differentiation at peak responses after immunization but accounted for an increased contraction phase manifesting as a larger loss of CXCR5 expression. Mechanistically, cells activated at a lower initial density had more sustained mammalian target of rapamycin complex 1 (mTORC1) activities that impair CXCR5 maintenance. YAP-dependent regulation of SLC7A5 involved in the cell density-dependent regulation of mTORC1 activities and TFH loss. Old mice fed with a leucine-restricted diet after peak responses showed smaller TFH loss and improved humoral immune responses. Attenuating mTORC1 signaling after peak response is a strategy to boost vaccine responses in older individuals.

The vascular aging process accelerated by type 2 diabetes mellitus (T2DM) is responsible for the elevated risk of associated cardiovascular diseases. Metabolic disorder-induced immune senescence has been implicated in multi-organ/tissue damage. Herein, we sought to determine the role of immunosenescence in diabetic vascular aging and to investigate the underlying mechanisms.

Aging hallmarks of the immune system appear prior to the vasculature in streptozotocin (STZ)/high-fat diet (HFD)-induced T2DM mice or db/db mice. Transplantation of aged splenocytes or diabetic splenocytes into young mice triggered vascular senescence and injury compared with normal control splenocyte transfer. RNA sequencing profile and validation in immune tissues revealed that the toll-like receptor 4-nuclear factor-kappa B-NLRP3 axis might be the mediator of diabetic premature immunosenescence. The absence of Nlrp3 attenuated immune senescence and vascular aging during T2DM. Importantly, senescent immune cells, particularly T cells, provoked perivascular adipose tissue (PVAT) dysfunction and alternations in its secretome, which in turn impair vascular biology. In addition, senescent immune cells may uniquely affect vasoconstriction via influencing PVAT. Lastly, rapamycin alleviated diabetic immune senescence and vascular aging, which may be partly due to NLRP3 signalling inhibition.

These results indicated that NLRP3 inflammasome-mediated immunosenescence precedes and drives diabetic vascular aging. The contribution of senescent immune cells to vascular aging is a combined effect of their direct effects and induction of PVAT dysfunction, the latter of which can uniquely affect vasoconstriction. We further demonstrated that infiltration of senescent T cells in PVAT was increased and associated with PVAT secretome alterations. Our findings suggest that blocking the NLRP3 pathway may prevent early immunosenescence and thus mitigate diabetic vascular aging and damage, and targeting senescent T cells or PVAT might also be the potential therapeutic approach.

The complex interplay between cancer progression and immune senescence is critically influenced by metabolic reprogramming in T cells. As T cells age, especially within the tumor microenvironment, they undergo significant metabolic shifts that may hinder their proliferation and functionality. This manuscript reviews how metabolic alterations contribute to T cell senescence in cancer and discusses potential therapeutic strategies aimed at reversing these metabolic changes. We explore interventions such as mitochondrial enhancement, glycolytic inhibition, and lipid metabolism adjustments that could rejuvenate senescent T cells, potentially restoring their efficacy in tumor suppression. This review also focuses on the significance of metabolic interventions in T cells with aging and further explores the future direction of the metabolism-based cancer immunotherapy in senescent T cells.

Splenic T cells are pivotal to the immune system, yet their function deteriorates with age. To elucidate the specific aspects of T cell biology affected by aging, we conducted a comprehensive multi-time point single-cell RNA sequencing study, complemented by single-cell Assay for Transposase Accessible Chromatin (ATAC) sequencing and single-cell T cell repertoire (TCR) sequencing on splenic T cells from mice across 10 different age groups. This map of age-related changes in the distribution of T cell lineages and functional states reveals broad changes in T cell function and composition, including a prominent enrichment of Gzmk+ T cells in aged mice, encompassing both CD4+ and CD8+ T cell subsets. Notably, there is a marked decrease in TCR diversity across specific T cell populations in aged mice. We identified key pathways that may underlie the perturbation of T cell functions with aging, supporting cytotoxic T cell clonal expansion with age. This study provides insights into the aging process of splenic T cells and also highlights potential targets for therapeutic intervention to enhance immune function in the elderly. The dataset should serve as a resource for further research into age-related immune dysfunction and for identifying potential therapeutic strategies.

This 48-week decentralized, double-blinded, randomized, placebo-controlled trial (NCT04488601) evaluated the long-term safety of intermittent low-dose rapamycin in a healthy, normative-aging human cohort. Participants received placebo, 5 mg or 10 mg compounded rapamycin weekly. The primary outcome measure was visceral adiposity (by DXA scan), secondary outcomes were blood biomarkers, and lean tissue and bone mineral content (by DXA scan). Established surveys were utilized to evaluate health and well-being. Safety was assessed through adverse events and blood biomarker monitoring.

Adverse and serious adverse events were similar across all groups. Visceral adiposity did not change significantly (ηp2 = 0.001, p = 0.942), and changes in blood biomarkers remained within normal ranges. Lean tissue mass (ηp2 = 0.202, p = 0.013) and self-reported pain (ηp2 = 0.168, p = 0.015) improved significantly for women using 10 mg rapamycin. Self-reported emotional well-being (ηp2 = 0.108, p = 0.023) and general health (ηp2 = 0.166, p = 0.004) also improved for those using 5 mg rapamycin. No other significant effects were observed.

Low-dose, intermittent rapamycin administration over 48 weeks is relatively safe in healthy, normative-aging adults, and was associated with significant improvements in lean tissue mass and pain in women. Future work will evaluate benefits of a broader range of rapamycin doses on healthspan metrics for longevity, and will aim to more comprehensively establish efficacy.

Thin endometrium is defined as an endometrial thickness of less than 7 mm in the midluteal phase of the menstrual cycle, a condition often seen in women of childbearing age with a history of uterine trauma, such as dilation and curettage or intrauterine adhesion separation. This inadequate thickness poses a substantial threat to endometrial receptivity and subsequent pregnancy, particularly during infertility treatments. Despite efforts to stimulate endometrial growth through agents such as high doses of estrogen, improvements in both endometrial thickness and pregnancy rates have been marginal. Consequently, it is referred to as "unresponsive endometrium or refractory thin endometrium." To explore novel therapeutic avenues, a deeper understanding of the underlying mechanisms is urgently needed. In this review, we examine recent single-cell sequencing studies that have identified key alterations in cell populations, signaling pathways, and cell-cell communication in the endometrium during the late proliferative phase, comparing normal endometrium and thin endometrium following uterine injuries. Evidence suggests that endometrial injury acted as a primary contributor, initiating an accelerated aging process across diverse cell types and establishing an environment characterized by immune incompetence and dysfunction. Senescence, a consequence of this injury, may impede endometrial proliferation, disrupt vascular development, and lead to fibrosis, creating a milieu of abnormal receptivity-a critical downstream event associated with implantation failure and infertility. Addressing these identified challenges necessitates advancing research to comprehend and target the key factors contributing to thin endometrium, a crucial step for clinical translation.

Immunity declines with age. This results in a higher risk of age-related diseases, diminished ability to respond to new infections and reduced response to vaccines. The causes of this immune dysfunction are cellular senescence, which occurs in both lymphoid and non-lymphoid tissue, and chronic, low-grade inflammation known as 'inflammageing'. In this Review article, we highlight how the processes of inflammation and senescence drive each other, leading to loss of immune function. To break this cycle, therapies are needed that target the interactions between the altered tissue environment and the immune system instead of targeting each component alone. We discuss the relative merits and drawbacks of therapies that are directed at eliminating senescent cells (senolytics) and those that inhibit inflammation (senomorphics) in the context of tissue niches. Furthermore, we discuss therapeutic strategies designed to directly boost immune cell function and improve immune surveillance in tissues.

Mitochondrial dynamics, governed by fusion and fission, are crucial for maintaining cellular homeostasis, energy production, and stress adaptation. MFN2 and OPA1, key regulators of mitochondrial fusion, play essential roles beyond their structural functions, influencing bioenergetics, intracellular signaling, and quality control mechanisms such as mitophagy. Disruptions in these processes, often caused by MFN2 or OPA1 mutations, are linked to neurodegenerative diseases like Charcot-Marie-Tooth disease type 2A (CMT2A) and autosomal dominant optic atrophy (ADOA). This review explores the molecular mechanisms underlying mitochondrial fusion, the impact of MFN2 and OPA1 dysfunction on oxidative phosphorylation and autophagy, and their role in disease progression. Additionally, we discuss the divergent cellular responses to MFN2 and OPA1 mutations, particularly in terms of proliferation, senescence, and metabolic signaling. Finally, we highlight emerging therapeutic strategies to restore mitochondrial integrity, including mTOR modulation and autophagy-targeted approaches, with potential implications for neurodegenerative disorders.

Ageing is an inevitable biological process that impacts the immune system, leading to immunosenescence and inflammaging, which contribute to increased susceptibility to infections, autoimmune diseases and cancers in individuals over the age of 65. This review focuses on the ageing of lymph node stromal cells (LNSCs), which are crucial for maintaining lymph node (LN) structure and function. Age-related changes in LNs, such as fibrosis and lipomatosis, disrupt the LN architecture and reduce immune cell recruitment and function, impairing immune responses to infections and vaccinations. The review discusses the structural and functional decline of various LNSC subsets, including fibroblastic reticular cells (FRCs), lymphatic endothelial cells (LECs) and blood endothelial cells (BECs), highlighting their roles in immune cell activation and homeostasis. Potential strategies to restore aged LNSC function, such as enhancing LNSC activation during vaccination and using senotherapeutics, are explored. Outstanding questions regarding the mechanisms of LNSC ageing and how ageing of the LN stroma might impact autoimmune disorders are also addressed. This review aims to stimulate further research into the characterisation of aged LNSCs and the development of therapeutic interventions to improve immune function in the older adults.

Research into aging constitutes a pivotal endeavor aimed at elucidating the underlying biological mechanisms governing aging and age-associated diseases, as well as promoting healthy longevity. Recent advances in transcriptomic technologies, such as bulk RNA sequencing (RNA-seq), single-cell transcriptomics, and spatial transcriptomics, have revolutionized our ability to study aging at unprecedented resolution and scale. These technologies present novel opportunities for the discovery of biomarkers, elucidation of molecular pathways, and development of targeted therapeutic strategies for age-related disorders. This review surveys recent breakthroughs in different types of transcripts on aging, such as mRNA, long noncoding (lnc)RNA, tRNA, and miRNA, highlighting key findings and discussing their potential implications for future studies in this field.

Companion dogs are a powerful model for aging research given their morphologic and genetic variability, risk for age-related disease, and habitation of the human environment. In addition, the shorter life expectancy of dogs compared to human beings provides a unique opportunity for an accelerated timeline to test interventions that might extend healthy lifespan. The Test of Rapamycin In Aging Dogs (TRIAD) randomized clinical trial is a parallel-group, double-masked, randomized, placebo-controlled, multicenter trial that will test the ability of rapamycin to prolong lifespan and improve several healthspan metrics in healthy, middle-aged dogs recruited from Dog Aging Project participants. Here, we describe the rationale, design, and goals of the TRIAD randomized clinical trial, the first rigorous test of a pharmacologic intervention against biological aging with lifespan and healthspan metrics as endpoints to be performed outside of the laboratory in any species.

Chimeric antigen receptor (CAR) T cell therapy shows promise for various diseases. Our studies in humanized mice and nonhuman primates demonstrate that hematopoietic stem cells (HSCs) modified with anti-HIV CAR achieve lifelong engraftment, providing functional antiviral CAR-T cells that reduce viral rebound after antiretroviral therapy (ART) withdrawal. However, T cell exhaustion due to chronic immune activation remains a key obstacle to sustained CAR-T efficacy, necessitating additional measures to achieve functional cure. We recently showed that low-dose rapamycin treatment reduced inflammation and improved anti-HIV T cell function in HIV-infected humanized mice. Here, we report that rapamycin improved CAR-T cell function both in vitro and in vivo. In vitro treatment with rapamycin enhanced CAR-T cell mitochondrial respiration and cytotoxicity. In vivo treatment with low-dose rapamycin in HIV-infected, CAR-HSC mice decreased chronic inflammation, prevented exhaustion of CAR-T cells, and improved CAR-T control of viral replication. RNA-sequencing analysis of CAR-T cells from humanized mice showed that rapamycin downregulated multiple checkpoint inhibitors and upregulated key survival genes. Mice treated with CAR-HSCs and rapamycin had delayed viral rebound after ART and reduced HIV reservoir compared with those treated with CAR-HSCs alone. These findings suggest that HSC-based anti-HIV CAR-T cells combined with rapamycin treatment are a promising approach for treating persistent inflammation and improving immune control of HIV replication.

Precisely assessing an individual's immune age is critical for developing targeted aging interventions. Although traditional methods for evaluating biological age, such as the use of cellular senescence markers and physiological indicators, have been widely applied, these methods inherently struggle to capture the full complexity of biological aging. We propose the concept of an 'immunosenescence clock' that evaluates immune system changes on the basis of changes in immune cell abundance and omics data (including transcriptome and proteome data), providing a complementary indicator for understanding age-related physiological transformations. Rather than claiming to definitively measure biological age, this approach can be divided into a biological age prediction clock and a mortality prediction clock. The main function of the biological age prediction clock is to reflect the physiological state through the transcriptome data of peripheral blood mononuclear cells (PBMCs), whereas the mortality prediction clock emphasizes the ability to identify people at high risk of mortality and disease. We hereby present nearly all of the immunosenescence clocks developed to date, as well as their functional differences. Critically, we explicitly acknowledge that no single diagnostic test can exhaustively capture the intricate changes associated with biological aging. Furthermore, as these biological functions are based on the acceleration or delay of immunosenescence, we also summarize the factors that accelerate immunosenescence and the methods for delaying it. A deep understanding of the regulatory mechanisms of immunosenescence can help establish more accurate immune-age models, providing support for personalized longevity interventions and improving quality of life in old age.

Belatacept, a fusion protein combining cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the Fc region of human IgG1, is increasingly used as a calcineurin inhibitor-sparing regimen in patients with chronic graft dysfunction. Older kidney transplant recipients, particularly from expanded criteria donors, may be switched to belatacept due to poor renal recovery. However, late-onset cytomegalovirus (CMV) reactivation is increasingly reported with this treatment, especially in older patients with graft dysfunction. This suggests a progressive loss of CMV-specific T cell response, potentially driven by T cell exhaustion. Contributing factors include preexisting T cell dysfunction, increased viral antigen exposure, and interference in the PD-L1/PD-1 pathway by belatacept. mTOR inhibitors have shown efficacy in preventing CMV reactivation by reinvigorating CMV-specific T cells. These findings support combining belatacept with mTOR inhibitors in high-risk CMV-seropositive recipients and emphasize the need for personalized immune assessments to guide immunosuppressive strategies.

Aging significantly diminishes T cell immunity, increasing susceptibility to infections and reducing vaccine efficacy in older individuals. Metabolism plays a key role in T cell function, shaping their energy requirements, activation, and differentiation. Recent studies highlight altered metabolic signaling as a pivotal factor in T cell aging, influencing the ability of T cells to maintain quiescence, respond to activation, and differentiate into functional subsets. Aberrant metabolic pathways disrupt the quiescence of aged T cells and skew their differentiation toward short-lived, pro-inflammatory effector T cells while hindering the generation of long-lived memory and T follicular helper cells. These changes contribute to a hyper-inflammatory state, exacerbate chronic low-grade inflammation, and compromise immune homeostasis. In this review, we explore how metabolic signaling is altered during T cell aging and the resulting functional impacts. We also discuss therapeutic approaches aimed at restoring proper T cell differentiation, improving vaccine responses, and rejuvenating immune function in older populations.

In this review, we review the current status of biomarkers for aging and possible perspectives on anti-aging or rejuvenation from the standpoint of biomarkers. Aging is observed in all cells and organs, and we focused on research into senescence in the skin, musculoskeletal system, immune system, and cardiovascular system. Commonly used biomarkers include SA-βgal, cell-cycle markers, senescence-associated secretory phenotype (SASP) factors, damage-associated molecular patterns (DAMPs), and DNA-damage-related markers. In addition, each organ or cell has its specific markers. Generally speaking, a combination of biomarkers is required to define age-related changes. When considering the translation of basic research, biomarkers that are highly sensitive, highly specific, with validation and reliability as well as being non-invasive are optimal; however, currently reported markers do not fulfill the prerequisite for biomarkers. In addition, rodent models of aging do not necessarily represent human aging, and markers in rodent or cell models are not applicable in clinical settings. The prerequisite of clinically applicable biomarkers is that they provide useful information for clinical decision-making, such as predicting disease risk, diagnosing disease, monitoring disease progression, or guiding treatment decisions. Therefore, the development of non-invasive robust, reliable, and useful biomarkers in humans is necessary to develop anti-aging therapy for humans. Geriatr Gerontol Int 2025; 25: 139-147.

Cardiovascular and cardiometabolic diseases are leading causes of morbidity and mortality worldwide, driven in part by chronic inflammation. Emerging research suggests that the bone marrow microenvironment, or marrow niche, plays a critical role in both immune system regulation and disease progression. The bone marrow niche is essential for maintaining hematopoietic stem cells (HSCs) and orchestrating hematopoiesis. Under normal conditions, this niche ensures a return to immune homeostasis after acute stress. However, in the setting of inflammatory conditions such as those seen in cardiometabolic diseases, it becomes dysregulated, leading to enhanced myelopoiesis and immune activation. This review explores the reciprocal relationship between the bone marrow niche and cardiometabolic diseases, highlighting how alterations in the niche contribute to disease development and progression. The niche regulates HSCs through complex interactions with stromal cells, endothelial cells, and signaling molecules. However, in the setting of chronic diseases such as hypertension, atherosclerosis, and diabetes, inflammatory signals disrupt the balance between HSC self-renewal and differentiation, promoting the excessive production of proinflammatory myeloid cells that exacerbate the disease. Key mechanisms discussed include the effects of hyperlipidemia, hyperglycemia, and sympathetic nervous system activation on HSC proliferation and differentiation. Furthermore, the review emphasizes the role of epigenetic modifications and metabolic reprogramming in creating trained immunity, a phenomenon whereby HSCs acquire long-term proinflammatory characteristics that sustain disease states. Finally, we explore therapeutic strategies aimed at targeting the bone marrow niche to mitigate chronic inflammation and its sequelae. Novel interventions that modulate hematopoiesis and restore niche homeostasis hold promise for the treatment of cardiometabolic diseases. By interrupting the vicious cycle of inflammation and marrow dysregulation, such therapies may offer new avenues for reducing cardiovascular risk and improving patient outcomes.

Rapamycin, also known as sirolimus, has demonstrated great potential for application in longevity medicine. However, the dynamics of low-dose rapamycin bioavailability, and any differences in bioavailability for different formulations (e.g., compounded or commercial), remain poorly understood. We thus explored rapamycin bioavailability in two real-world cohorts to begin providing a foundational understanding of differences in effects between formulations over time. The small trial study cohort was utilized to explore the blood rapamycin levels of commercial (n = 44, dosages 2, 3, 6, or 8 mg) or compounded (n = 23, dosages 5, 10, or 15 mg) rapamycin 24 h after dose self-administration. Results suggested dose-to-blood level relationships were linear for both formulations, though compounded had a lower bioavailability per milligram of rapamycin (estimated to be 31.03% of the same dose of commercial). While substantial inter-individual heterogeneity in blood rapamycin levels was observed for both formulations, repeat tests for individuals over time demonstrated relative consistency. Extending exploration to 316 real-world longevity rapamycin users from the AgelessRx Observational Research Database produced similar findings, and additionally suggested that blood rapamycin levels peak after 2 days with gradual decline thereafter. Taken together, our findings suggest that individualized dosing and routine monitoring of blood rapamycin levels should be utilized to ensure optimal dosing and efficacy for healthy longevity.

The untimely passing of Dr. Mikhail "Misha" Blagosklonny has left a lasting void in geroscience and oncology. This review examines his profound contributions, focusing on his pioneering the Hyperfunction Theory and his advocacy for rapamycin, an mTOR inhibitor, as a therapeutic agent for lifespan extension. Contrary to traditional damage-centric models, the Hyperfunction Theory rejects damage accumulation as the primary driver of aging. Instead, it redefines aging as a quasi-programmed process driven by the persistent, excessive activity of growth-promoting pathways beyond their developmental roles, leading to age-related pathologies. We explore how Blagosklonny's insights predict rapamycin's ability to decelerate aging by modulating excessive mTOR signaling, supported by empirical evidence across multiple physiological systems, including immune, cardiovascular, cognitive, and oncologic health. His forward-thinking approach, advocating for the cautious clinical use of rapamycin and suggesting personalized, preventive, and combination therapy strategies, has catalyzed interest in translational geroscience. This review synthesizes Blagosklonny's legacy, presenting rapamycin as a foundational pharmacological intervention with potential in managing age-related decline and extending healthspan, and underlines his impact in shifting aging research from theoretical frameworks to actionable interventions. Blagosklonny's work remains an enduring inspiration, paving the way toward treating aging as a modifiable condition.

Increased entropy is a common cause of disease and aging. Lifespan entropy is the overall increase in disorder caused by a person over their lifetime. Aging leads to the excessive production of reactive oxygen species (ROS), which damage the antioxidant system and disrupt redox balance. Organ aging causes chronic inflammation, disrupting the balance of proinflammatory and anti-inflammatory factors. Inflammaging, which is a chronic low-grade inflammatory state, is activated by oxidative stress and can lead to immune system senescence. During this process, entropy increases significantly as the body transitions from a state of low order to high disorder. However, the connection among inflammation, aging, and immune system activity is still not fully understood. This review introduces the idea of the ROS-inflammation-immune balance for the first time and suggests that this balance may be connected to aging and the development of age-related diseases. We also explored how the balance of these three factors controls and affects age-related diseases. Moreover, imbalance in the relationship described above disrupts the regular structures of cells and alters their functions, leading to cellular damage and the emergence of a disorganized state marked by increased entropy. Maintaining a low entropy state is crucial for preventing and reversing aging processes. Consequently, we examined the current preclinical evidence for antiaging medications that target this balance. Ultimately, comprehending the intricate relationships between these three factors and the risk of age-related diseases in organisms will aid in the development of clinical interventions that promote long-term health.

This article is a summary of the first AGS Symposium entitled "Update on Vaccination Strategies for Older Adults: Matching the Approach to the Individual and the Care Setting." Given declines in host defenses and immune function with aging, vaccinations play a pivotal role in fortifying older adults against preventable infections, resulting diseases, disability, and death. Current guidelines generally list recommendations applicable for an average older adult of a given chronological age. However, growing evidence indicates that heterogeneity in terms of factors as varied as biological sex, frailty, functional status, and multimorbidity may impact vaccine responses and clinical outcomes. As a result, clinicians will increasingly need to take these additional factors into consideration as they seek to improve outcomes through improved targeting of such aging-related heterogeneity. Moreover, efforts at protecting older citizens through vaccination must also include strategies to overcome barriers to the adoption of vaccine recommendations in varied settings including long-term care. This 2023 AGS Plenary Symposium sought to commence a broader dialogue across AGS and beyond on optimizing vaccinations for older adults, ensuring not only extended lifespans but also healthier and more active lives. This report is not a systematic review, and thus should not be considered comprehensive.

Immunosenescence, the age-related decline in immune function, is a complex biological process with profound implications for health and longevity. This phenomenon, characterized by alterations in both innate and adaptive immunity, increases susceptibility to infections, reduces vaccine efficacy, and contributes to the development of age-related diseases. At the cellular level, immunosenescence manifests as decreased production of naive T and B cells, accumulation of memory and senescent cells, thymic involution, and dysregulated cytokine production. Recent advances in molecular biology have shed light on the underlying mechanisms of immunosenescence, including telomere attrition, epigenetic alterations, mitochondrial dysfunction, and changes in key signaling pathways such as NF-κB and mTOR. These molecular changes lead to functional impairments in various immune cell types, altering their proliferative capacity, differentiation, and effector functions. Emerging research suggests that lifestyle factors may modulate the rate and extent of immunosenescence at both cellular and molecular levels. Physical activity, nutrition, stress management, and sleep patterns have been shown to influence immune cell function, inflammatory markers, and oxidative stress in older adults. This review provides a comprehensive analysis of the molecular and cellular mechanisms underlying immunosenescence and explores how lifestyle interventions may impact these processes. We will examine the current understanding of immunosenescence at the genomic, epigenomic, and proteomic levels, and discuss how various lifestyle factors can potentially mitigate or partially reverse aspects of immune aging. By integrating recent findings from immunology, gerontology, and molecular biology, we aim to elucidate the intricate interplay between lifestyle and immune aging at the molecular level, potentially informing future strategies for maintaining immune competence in aging populations.

The chronic inflammation present in aged individuals is generally depicted as a detrimental player for longevity. Here, it is discussed several beneficial effects associated with the cytokines that are chronically elevated in inflammaging. These cytokines, such as IL-1β, type I interferons, IL-6 and TNF positively regulate macroautophagy, mitochondrial function, anti-tumor immune responses and skeletal muscle biogenesis, possibly contributing to longevity. On the other side, the detrimental and antagonistic role of these cytokines including the induction of sarcopenia, tissue damage and promotion of tumorigenesis are also discussed, underscoring the dichotomy associated with inflammaging and its players. In addition, it is discussed the role of the anti-inflammatory cytokine IL-10 and other cytokines that affect aging in a more linear way, such as IL-11, which promotes senescence, and IL-4 and IL-15, which promotes longevity. It is also discussed more specific regulators of aging that are downstream cytokines-mediated signaling.

Aging is associated with the onset and progression of multiple diseases, which limit health span. Chronic low-grade inflammation in the absence of overt infection is considered the simmering source that triggers age-associated diseases. Failure of many cellular processes during aging is mechanistically linked to inflammation; however, the overall decline in the cellular homeostasis mechanism of autophagy has emerged as one of the top and significant inducers of inflammation during aging, frequently known as inflammaging. Thus, physiological or pharmacological interventions aimed at improving autophagy are considered geroprotective. Rapamycin analogs (rapalogs) are known for their ability to inhibit mTOR and thus regulate autophagy. This study assessed the efficacy of everolimus, a rapalog, in regulating inflammatory cytokine production in T cells from older adults. CD4+ T cells from older adults were treated with a physiological dose of everolimus (0.01 µM), and indices of autophagy and inflammation were assessed to gain a mechanistic understanding of the effect of everolimus on inflammation. Everolimus (Ever) upregulated autophagy and broadly alleviated inflammatory cytokines produced by multiple T cell subsets. Everolimus's ability to alleviate the cytokines produced by Th17 subsets of T cells, such as IL-17A and IL-17F, was dependent on autophagy and antioxidant signaling pathways. Repurposing the antineoplastic drug everolimus for curbing inflammaging is promising, given the drug's ability to restore multiple cellular homeostasis mechanisms.

Tuberculosis (TB) is one of the leading causes of death due to infectious disease. It is a treatable disease; however, conventional treatment requires a lengthy treatment regimen with severe side effects, resulting in poor compliance among TB patients. Intermittent drug use, the non-compliance of patients, and prescription errors, among other factors, have led to the emergence of multidrug-resistant TB, while the mismanagement of multidrug-resistant TB (MDR-TB) has eventually led to the development of extensively drug-resistant tuberculosis (XDR-TB). Thus, there is an urgent need for new drug development, but due to the enormous expenses and time required (up to 20 years) for new drug research and development, new therapeutic approaches to TB are required. Host-directed therapies (HDT) could be a most attractive strategy, as they target the host defense processes instead of the microbe and thereby may prevent the alarming rise of MDR- and XDR-TB. This paper reviews the progress in HDT for the treatment of TB using repurposed drugs which have been investigated in clinical trials (completed or ongoing) and plant-derived natural products that are in clinical or preclinical trial stages. Additionally, this review describes the existing challenges to the development and future research directions in the implementation of HDT.

The biological progression of aging encompasses complex physiological processes. As individuals grow older, their physiological functions gradually decline, including compromised immune responses, leading to immunosenescence. Immunosenescence significantly elevates disease susceptibility and severity in older populations while concurrently compromising vaccine-induced immune responses. This comprehensive review aims to elucidate the implications of immunosenescence for vaccine-induced immunity and facilitate the development of optimized vaccination strategies for geriatric populations, with specific focus on COVID-19, influenza, pneumococcal, herpes zoster, and respiratory syncytial virus (RSV) vaccines. This review further elucidates the relationship between immunosenescence and vaccine-induced immunity. This review presents a systematic evaluation of intervention strategies designed to enhance vaccine responses in older populations, encompassing adjuvant utilization, antigen doses, vaccination frequency modification, inflammatory response modulation, and lifestyle interventions, including physical activity and nutritional modifications. These strategies are explored for their potential to improve current vaccine efficacy and inform the development of next-generation vaccines for geriatric populations.

Aging is the result of a complex interplay of physical, environmental, and social factors, leading to an increased prevalence of chronic age-related diseases that burden health and social care systems. As the global population ages, it is crucial to understand the aged immune system, which undergoes declines in both innate and adaptive immunity. This immune decline exacerbates the aging process, creating a feedback loop that accelerates the onset of diseases, including infectious diseases, autoimmune disorders, and cancer. Intervention strategies, including dietary adjustments, pharmacological treatments, and immunomodulatory therapies, represent promising approaches to counteract immunosenescence. These interventions aim to enhance immune function by improving the activity and interactions of aging-affected immune cells, or by modulating inflammatory responses through the suppression of excessive cytokine secretion and inflammatory pathway activation. Such strategies have the potential to restore immune homeostasis and mitigate age-related inflammation, thus reducing the risk of chronic diseases linked to aging. In summary, this review provides insights into the effects and underlying mechanisms of immunosenescence, as well as its potential interventions, with particular emphasis on the relationship between aging, immunity, and nutritional factors.

Chronic or non-healing wounds, such as diabetic foot ulcers (DFUs), venous leg ulcers (VLUs), pressure ulcers (PUs) and wounds in the elderly etc., impose significant biological, social, and financial burdens on patients and their families. Despite ongoing efforts, effective treatments for these wounds remain elusive, costing the United States over US$25 billion annually. The wound healing process is notably slower in the elderly, partly due to cellular senescence, which plays a complex role in wound repair. High glucose levels, reactive oxygen species, and persistent inflammation are key factors that induce cellular senescence, contributing to chronic wound failure. This suggests that cellular senescence may not only drive age-related phenotypes and pathology but also be a key mediator of the decreased capacity for trauma repair. This review analyzes four aspects: characteristics of cellular senescence; cytotoxic stressors and related signaling pathways; the relationship between cellular senescence and typical chronic non-healing wounds; and current and future treatment strategies. In theory, anti-aging therapy may influence the process of chronic wound healing. However, the underlying molecular mechanism is not well understood. This review summarizes the relationship between cellular senescence and chronic wound healing to contribute to a better understanding of the mechanisms of chronic wound healing.

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a pivotal role in various biological processes, through integrating external and internal signals, facilitating gene transcription and protein translation, as well as by regulating mitochondria and autophagy functions. mTOR kinase operates within two distinct protein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which engage separate downstream signaling pathways impacting diverse cellular processes. Although mTORC1 has been extensively studied as a pro-proliferative factor and a pro-aging hub if activated aberrantly, mTORC2 received less attention, particularly regarding its implication in aging regulation. However, recent studies brought increasing evidence or clues for us, which implies the associations of mTORC2 with aging, as the genetic elimination of unique subunits of mTORC2, such as RICTOR, has been shown to alleviate aging progression in comparison to mTORC1 inhibition. In this review, we first summarized the basic characteristics of mTORC2, including its protein architecture and signaling network. We then focused on reviewing the molecular signaling regulation of mTORC2 in cellular senescence and organismal aging, and proposed the multifaceted regulatory characteristics under senescent and nonsenescent contexts. Next, we outlined the research progress of mTOR inhibitors in the field of antiaging and discussed future prospects and challenges. It is our pleasure if this review article could provide meaningful information for our readers and call forth more investigations working on this topic.

A healthy lifespan relies on independent living, in which active skeletal muscle is a critical element. The cost of not recognizing and acting earlier on unhealthy or aging muscle could be detrimental, since muscular weakness is inversely associated with all-cause mortality. Sarcopenia is characterized by a decline in skeletal muscle mass and strength and is associated with aging. Exercise is the only effective therapy to delay sarcopenia development and improve muscle health in older adults. Although numerous interventions have been proposed to reduce sarcopenia, none has yet succeeded in clinical trials. This review evaluates the biological gap between recent clinical trials targeting sarcopenia and the preclinical studies on which they are based, and suggests an alternative approach to bridge the discrepancy.

Sepsis is a systemic inflammatory response syndrome caused by a dysregulated host response to infection. CD4+T cell reduction is crucial to sepsis-induced immunosuppression. Pyroptosis, a programmed necrosis, is concerned with lymphocytopenia. Peroxisome proliferator-activated receptor gamma (PPARγ) regulated by upstream mTOR, exerts anti-pyroptosis effects. To investigate the potential effects of mTOR-PPARγ on sepsis-induced CD4+T cell depletion and the underlying mechanisms, we observed mTOR activation and pyroptosis with PPARγ-Nrf suppression through cecal ligation and puncture (CLP) sepsis mouse model. Further mechanism research used genetically modified mice with T cell-specific knockout mTOR or Tuberous Sclerosis Complex1 (TSC1). It revealed that mTOR mediated CD4 + T cell pyroptosis in septic mice by negatively regulating the PPARγ-Nrf2 signaling pathway. Taken together, mTOR-PPARγ-Nrf2 signaling mediated the CD4+ T cell pyroptosis in sepsis, contributing to CD4+T cell depletion and immunosuppression.

As we age, our immune system's ability to effectively respond to pathogens declines, a phenomenon known as immunosenescence. This age-related deterioration affects both innate and adaptive immunity, compromising immune function and leading to chronic inflammation that accelerates aging. Immunosenescence is characterized by alterations in immune cell populations and impaired functionality, resulting in increased susceptibility to infections, diminished vaccine efficacy, and higher prevalence of age-related diseases. Chronic low-grade inflammation further exacerbates these issues, contributing to a decline in overall health and resilience. This review delves into the characteristics of immunosenescence and examines the various intrinsic and extrinsic factors contributing to immune aging and how the hallmarks of aging and cell fates can play a crucial role in this process. Additionally, it discusses the impact of sex, age, social determinants, and gut microbiota health on immune aging, illustrating the complex interplay of these factors in altering immune function. Furthermore, the concept of immune resilience is explored, focusing on the metrics for assessing immune health and identifying strategies to enhance immune function. These strategies include lifestyle interventions such as diet, regular physical activity, stress management, and the use of gerotherapeutics and other approaches. Understanding and mitigating the effects of immunosenescence are crucial for developing interventions that support robust immune responses in aged individuals.