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PubMed2025

Targeting innovative therapeutic approaches to the hallmarks of aging to combat Alzheimer's disease.

Aging is the leading risk factor for neurodegenerative diseases, including Alzheimer's disease. Mounting evidence implicates twelve interconnected hallmarks of aging, such as genomic instability, mitochondrial dysfunction, cellular senescence, and altered intercellular communication, as core contributors to cognitive decline. In this review, we will first delineate the hallmarks of aging and their mechanistic roles according to their functions in the aging brain and Alzheimer's disease. These hallmarks can be grouped into four major functional clusters: (i) Genomic and epigenomic instability, (ii) proteostasis and organelle dysfunction, (iii) cellular fate and regenerative decline, and (iv) cellular senescence. Then, we provide an overview of innovative therapeutic approaches aimed at modifying these hallmarks, focusing on the emerging paradigm of supplementation of rejuvenation factors that are derived from young plasma, stem cell secretomes, or their derivatives (e.g., extracellular vesicles). Finally, we discuss key aging-related biological factors that can influence Alzheimer's disease progression and evaluate their potential as therapeutic targets.

Alzheimer’s disease↗
PubMed2026

Ovarian aging and systemic health: Mechanisms and emerging intervention strategies.

Ovarian aging may contribute to systemic aging via the ovarian-systemic axis. This review outlines intrinsic ovarian cellular defects such as genomic instability, epigenetic shifts, and mitochondrial and proteostasis damage, which may trigger senescence-associated secretory phenotype (SASP)-related inflammaging, fibrosis, and distal pro-aging signals. Ovarian-derived endocrine disruption, especially estrogen decline, broadly affects bodily physiology. We summarize emerging multimodal interventions, including senolytics, metabolic reprogramming, regenerative medicine, and systemic approaches, and we discuss their dual potential to preserve fertility and intercept ovarian contributions to systemic aging. Ovarian aging is possibly associated with female age-related multimorbidity. Ovary-targeted prevention may extend healthspan, as assessed by combined reproductive and systemic clinical evaluations.

Humans↗
PubMed2026

Repair and regeneration across the lifespan: an ontogenetic perspective.

The capacity for tissue repair and regeneration undergoes a profound and progressive decline across the human lifespan, representing a fundamental driver of aging and chronic disease. This review establishes a comprehensive ontogenetic framework by mapping the continuous biological transition from the flawless, scarless regenerative plasticity of embryonic development to the irreversible fibrotic scarring and organ failure characteristic of senescence. We synthesize the hierarchical collapse of reparative networks across multiple biological scales. Importantly, this ontogenetic decline should not be interpreted as a purely degenerative trajectory but rather as a dynamic systems-level reprogramming in which evolutionary trade-offs prioritize tumor suppression, immune surveillance, and reproductive fitness over long-term regenerative fidelity. Recognizing this adaptive reallocation of biological resources reframes aging not simply as failure but as a predictable recalibration of repair hierarchies. At the molecular and cellular levels, the accumulation of genomic instability, unresolvable DNA damage, and mitochondrial dysfunction gradually overwhelms intracellular quality-control mechanisms. Concurrently, epigenetic drift and chronic, low-grade systemic inflammation ("inflammaging") dismantle the stem cell niche, driving adult stem cell exhaustion and shifting wound healing away from functional tissue replacement toward maladaptive fibrosis. Furthermore, we examine divergent, organ-specific repair trajectories. By contrasting the severe regenerative restrictions of the adult central nervous system and myocardium with the persistent, yet exhaustible, resilience of the liver, we elucidate the unique intrinsic and microenvironmental barriers that impede structural and functional recovery. Finally, we evaluate the clinical paradigm shift from passive management of age-related degeneration to active restoration of tissue integrity. By integrating systemic geroscience-which addresses the global hallmarks of aging-with targeted bioengineering and in vivo epigenetic modulation, contemporary regenerative medicine seeks to recreate permissive, youthful microenvironments. Ultimately, mastering these ontogenetic principles holds unprecedented potential to reactivate endogenous repair pathways, mitigate multi-organ collapse, and significantly extend human functional healthspan.

DNA repair↗
PubMed2026

Aging of hair follicle stem cells and their niche: mechanisms and regenerative therapeutic strategies.

Hair follicles (HFs) are vital skin appendages that perform fundamental functions including protection, thermoregulation, and sensation. Orchestrated by hair follicle stem cells (HFSCs), HFs undergo cyclic regeneration throughout the lifespan. However, during chronological aging, this mini-organ experiences progressive physiological decline, clinically characterized by a marked reduction in hair density and hair graying due to pigmentation dysfunction. This aging process involves HFSC exhaustion accompanied by diminished regenerative potential and differentiation capacity, leading to degenerative changes in the bulge architecture. Concurrently, the niche supporting HFSC homeostasis undergoes multi-dimensional and systemic degradation. This niche deterioration disrupts the delicate balance between HFSC quiescence and activation, further impeding hair regeneration. In this review, we delineate the dynamic anatomical changes throughout the hair growth cycle and describe the alterations of HFSCs during aging. We specifically focus on the mechanisms underlying the multi-dimensional degradation of the HFSC niche at tissue, cellular, and molecular levels. Furthermore, we discuss various therapeutic strategies aimed at ameliorating HF aging, offering potential insights for future clinical translation in hair regeneration. Finally, we propose that integrating spatiotemporal high-resolution technologies with genomic data to further decipher the spatiotemporal behaviors of aging HFSCs and niche cells will facilitate the establishment of a robust mechanistic framework for HFSC and niche aging.

Hair Follicle↗
PubMed2026

BACH1 orchestrates macrophage state transitions to coordinate regenerative inflammation.

Efficient tissue regeneration requires the precise coordination of inflammatory and regenerative programs, principally mediated by monocyte-derived macrophages. However, the transcriptional wiring and epigenomic processes behind complex macrophage subtype specification and transition between the different states are not known. Here we have identified the transcriptional repressor BACH1 as a critical, cell-intrinsic regulator of monocyte-derived macrophage specification during skeletal muscle regeneration. Using a myeloid-specific BACH1 knockout mouse model, we demonstrate that BACH1 deficiency disrupts the temporal coordination of monocyte-to-macrophage differentiation, leading to aberrant macrophage subsets with concurrent opposing pro- and anti-inflammatory features. Single-cell RNA-sequencing profiling reveals that BACH1 controls a core transcriptional network, including Nfkb1, Cebpb, and interferon signaling, governing inflammatory resolution and functional macrophage specialization. Mechanistically, BACH1 loss accelerates macrophage differentiation but also affects its core cellular identity, resulting in sustained, rather than declining inflammatory programs including upregulation of Il1b and thus, defective tissue remodeling. These immune alterations compromise the paracrine landscape during regenerative inflammation and impair muscle stem cell differentiation. Our findings establish BACH1 as a molecular tuner or controller that integrates early innate immune signaling with regenerative output, positioning it as a central node linking transcriptional control, immune fate decisions, and tissue repair.

Animals↗
PubMed1978

Factors influencing the quantity and quality of semen harvested from bulls, rams, boars and stallions.

Several inherited conditions associated with testicular defects, abnormal spermatogenesis and morphologically abnormal sperm have been found. These usually are controlled by single gene pairs. A notable exception is testicular size, with heritability in young bulls ranging from .42 to .88. Testicular size directly affects sperm output potential. The major contributor to variation in semen quality is the environment. Environmental effects may be temporary or permanent. Permanent effects occurring during prenatal and prepubertal periods and temporary or permanent factors acting after spermatogenesis is initiated can alter semen quality. Semen quality improves during the first few months after puberty and declines in old age. Malnutrition and the ingestion of toxic materials can have a major effect on testicular development and spermatogenesis, but the reproductive system has considerable regenerative capacity unless the dietary deficiencies are severe and prolonged. Elevated testicular temperatures resulting from incomplete descent of the testes (cryptorchidism), high environmental temperatures or inflammation are detrimental to spermatogenesis in all scrotal mammals. Cold temperatures appear to be innocuous unless actual freezing of tissue occurs. During periods of decreasing daylight semen quality declines in stallions and improves in seasonally breeding sheep. The time required to form and transport sperm in bulls, rams, boars and stallions is about 64, 56, 47 and 59 days. Therefore, a considerable potential lag may exist between a testicular event responsible for a change in semen quality and the time that this change is evident in ejaculated semen. Conditions imposed at the time of semen collection such as frequency of ejaculation, degree of sexual preparation and type of semen collection may influence the quality of semen harvested. Finally, certain semen characteristics are more variable than others and investigators should utilize suitable existing data to design the most effective least-cost experiments.

Animals↗
PubMed1978

Early decline of thymic effect on T cell differentiation.

Thymic lobes of B6C3F1 mice ranging in age from 1 day to 11 weeks were implanted under the kidney capsule of T cell deprived syngeneic young adult TXB mice, and the capacity of the thymus grafts to influence the maturation of T cells was assessed at 6 and 12 weeks after the implantation in terms of (a) regenerative activities of the grafted thymus, (2) splenic T cell dependent anti-SRBC response, and (c) mitogenic reactivity of spleen and lymph node cells to T cell specific mitogens. The results revealed that: (1) thymic tissues from 1 week old donors were most efficient in restoring the immune potential of adult TXB mice; (2) a decline in mitogenic reactivities of spleen and lymph node cells was observed in recipients of thymus grafts from donors of 1 month and older; and a decline of splenic helper T cell function was observed in recipients of thymus grafts from 11 weeks old donors. The significance of this early decline in the thymic effect on T cell differentiation is discussed.

Aging↗
PubMed2025

Aging and Corneal Nerve Health: Mechanisms of Degeneration and Emerging Therapies for the Cornea.

Corneal nerves play a crucial role in maintaining ocular surface homeostasis by supporting the functional integrity of corneal epithelial, stromal, and endothelial cells; modulating tear secretion; and facilitating sensory responses essential for overall ocular health. With advancing age, these highly specialized peripheral sensory fibers undergo progressive attrition and morphologic distortion driven by the canonical hallmarks of aging including genomic instability, impaired proteostasis, mitochondrial dysfunction, and chronic low-grade inflammation. The resulting neuro-immune dysregulation reduces trophic support, delays wound healing, and predisposes older adults to dry-eye disease, neurotrophic keratopathy, and postsurgical hypoesthesia. Age-exacerbating cofactors including diabetes, dyslipidemia, neurodegenerative disorders, topical preservatives, chronic contact-lens wear, herpes zoster ophthalmicus, and ocular-surface hypoxia further accelerate sub-basal nerve rarefaction and functional decline. This review provides an overview of age-related physiological alterations in ocular surface nerves, with a particular emphasis on corneal innervation. It also discusses risk factors that speed up these changes. Given the inherently limited regenerative capacity of corneal nerves and their inability to fully restore to baseline conditions following injury or degeneration, it is critical to identify and develop effective strategies aimed at mitigating or delaying physiological nerve degeneration and promoting nerve regeneration. This review also brings up emerging therapeutic strategies, including regenerative medicine, neuroprotective agents, and lifestyle interventions aimed at mitigating age-related corneal nerve degeneration.

Humans↗
PubMed1975

A fine structural study of degenerative-regenerative pathology in the surgically deafferentated lateral vestibular nucleus of the rat.

An experiment was designed to examine the course of degeneration, phagocytosis, and regeneration in the central nervous system following surgical deafferentation. The anterior cerebellar vermis was ablated in young male rats. The animals were sacrificed by perfusion at postoperative times ranging from 24 hrs to 6 months. The lateral vestibular nuclei, to which the anterior cerebellar vermis projects, were processed for electron microscopy. Degenerating synaptic terminals, of the dark variety, were seen from 24 hrs to five days postoperatively. Phagocytosis of degenerating terminals occurred during this time. Degenerating axons persisted through 6 months survival, and phagocytosis of these degenerating axons were observed. Astrocyte scar formation began at 1 month postoperatively. The relative number of axosomatic synaptic terminals containing flattened vesicles ("F" terminals; presumed inhibitory in function) increased in operated animals. The highest F scores were found from 24 hrs to two weeks postoperatively, and then the F scores declined through six months. The significance of these sprouting activities is discussed in relation to the abortive sprouting phenomenon described by Ramon y Cajal.

Animals↗
PubMed2026

Subjective cognition trajectories, Alzheimer biomarkers, and incident mild cognitive impairment.

BACKGROUND: Subjective cognitive decline is common in older adults and may represent an early clinical signal along the Alzheimer's disease continuum. The clinical relevance of longitudinal changes in subjective cognitive decline remains unclear. OBJECTIVES: To determine whether trajectories of self- or study partner-reported cognitive decline predict progression to mild cognitive impairment and reflect Alzheimer's disease-specific biological patterns. DESIGN, SETTING, PARTICIPANTS: Data were pooled from two observational cohorts. Cognitively unimpaired participants with baseline amyloid status, repeated assessments of subjective cognitive decline, and clinical follow-up were included. The study included 770 participants with a median follow-up of 5.0 years (interquartile range 4.0-7.0). MEASUREMENTS: Subjective cognitive decline was assessed using the Everyday Cognition questionnaire completed by participants and study partners. Linear mixed-effects models examined associations with amyloid status and progression to mild cognitive impairment. Cox proportional hazards models tested whether one-year changes predicted progression. RESULTS: Amyloid-positive participants and those who progressed to mild cognitive impairment showed steeper increases in self- and study partner-reported cognitive difficulties over time. Among amyloid-positive participants, only increases in study partner-report differentiated progressors from non-progressors. One-year increases in study partner-report predicted a higher risk of mild cognitive impairment compared with unchanged scores (hazard ratio 3.24; 95% confidence interval 1.73-6.07]), with effects confined to amyloid-positive participants. CONCLUSIONS: Short-term increases in study partner-reported cognitive difficulties identify amyloid-positive cognitively unimpaired older adults at increased risk of near-term progression to mild cognitive impairment. Longitudinal monitoring using study partner reports may provide a low-burden and clinically relevant approach for early risk stratification and surveillance in aging populations.

Humans↗
PubMed2026

Exerkine dysregulation links visceral adiposity to skeletal muscle impairment in end-stage heart failure with reduced ejection fraction: proteomic evidence for a cardio-adipose-muscle axis.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is associated with profound alterations in body composition, skeletal muscle dysfunction, and impaired exercise capacity. Exerkines representing exercise-responsive signaling molecules released by skeletal muscle, adipose tissue, and other organs may mediate systemic metabolic communication between tissues. However, their role in advanced HFrEF and their relationship with adiposity and skeletal muscle characteristics remain poorly understood. METHODS: We studied 73 patients with end-stage HFrEF and 16 healthy controls. Body composition was assessed using computed tomography, including visceral (VAT), subcutaneous (SAT), and epicardial adipose tissue (EAT), as well as skeletal muscle quantity (psoas muscle index, PMI) and quality (psoas muscle density, PMD). Functional performance was evaluated using handgrip strength (HGT) and the 6-min walk test (6MWT). Circulating exerkines were quantified using the Olink technology. Associations between proteins and clinical variables were assessed using age- and creatinine-adjusted linear models with false discovery rate correction. RESULTS: Among patients with HFrEF, 36% were obese and 38% exhibited central obesity independent of BMI. Muscle strength and muscle quality were strongly associated with functional capacity. VAT correlated with muscle mass but not with muscle quality or performance. Compared with controls, HFrEF patients demonstrated elevated inflammatory and metabolic stress-related exerkines including CXCL8, CCL2, IL-6, TNF, IL-15, GDF15, FGF21, ANGPTL4, CTSB, DCN, and resistin. In contrast, proteins associated with muscle integrity and regenerative signaling (myostatin, BDNF, IL-7, SPARC) were significantly reduced. In HFrEF patients leptin strongly correlated with adiposity measures. Metabolic stress mediators (GDF15, IL-15, FGF21, CTSB) were inversely associated with muscle quality and functional performance, whereas myostatin positively correlated with muscle quality, strength, and exercise capacity. BDNF was inversely associated with frailty. CONCLUSIONS: Advanced HFrEF is characterized by a dysregulated exerkine network linking adiposity, skeletal muscle quality, and functional performance. Four biologically coherent axes were identified: a leptin-driven adiposity axis, a metabolic stress-muscle quality axis, a myostatin-related muscle function axis, and a neurotrophic frailty axis. These findings support the presence of a systemic cardio-adipose-muscle signaling network in end-stage HFrEF and identify candidate molecular mediators of sarcopenia and functional decline.

Humans↗
PubMed1978

Effects of calcitonin on epidermal regeneration and collagen synthesis in rabbits with experimental wounds.

The cellular and metabolic effects induced by calcitonin on regenerative epidermal cells, fibroblasts and collagen fibers during wound healing were studied in rabbits. Electron microscopy revealed marked changes at 2 and 5 days post-wounding in epidermal cells and fibroblasts in calcitonin-treated rabbits such as: an increase in keratohyaline granules, tonofilaments, polysomes and a hypertrophy of nuclei in the epidermal cells. Fibroblasts are hypertrophied and surrounded by large areas of mature collagen fibers, namely at 5 and 14 days. Electron microscopic autoradiography revealed an increase in the incorporation of 3H-thymidine mostly in the nuclear chromatin, 3H-uridine in the nucleoli, 3H-leucine in the endoplasmic reticulum, polysomes and newly formed keratin layers, and 3H-proline over fibroblasts and collagen fibers. Most of the cellular and metabolic effects are evident at 2.5 hours and gradually decline by 5 and 24 hours of hormone administration. Scanning electron microscopy showed changes in the keratin pattern and collagen fibers. At 5 days after wounding and calcitonin treatment, a typical scaly pattern of keratin can be noted while in controls it is smooth and homogeneous. At 14 days post-wounding the collagen fibers are hypertrophied, with an extensive network of fibrils in calcitonin-treated rabbits. These findings demonstrate that synthetic salmon calcitonin stimulates protein synthesis, keratinogenesis and collagen formation in epidermal cells and fibroblasts during wound healing.

Animals↗
PubMed2026

YAP Promotes Microtubule Growth to Facilitate Sarcomere Disassembly in Adult Cardiomyocytes.

BACKGROUND: Mature mammalian cardiomyocytes (CMs) develop compact sarcomeric structures that inhibit proliferation. Consequently, CMs must dedifferentiate to a fetus-like state, which is accompanied by sarcomere disassembly, to enable successful cytokinesis. However, the regulation and coordination of CM dedifferentiation, cell cycle progression, and sarcomere reorganization remain unclear. METHODS: We generated adenovirus and adeno-associated virus (MyoAAV) vectors expressing YAP5SA and YAP5SA-S94A under Xon control for LMI070-inducible protein expression. We also developed MyoAAV-cTnT-Tuba1b-shRNA-miR30 for cardiomyocyte-specific knockdown of Tuba1b. These tools were used to investigate CM dedifferentiation and proliferation and sarcomere disassembly. We also performed Cleavage Under Targets and Release Using Nuclease to map the genome-wide binding sites of YAP5SA and YAP5SA-S94A in combination with RNA sequencing to identify YAP target genes. In addition, time-course live-imaging analysis was used to evaluate microtubule and sarcomere dynamics in adult CMs. RESULTS: We show that microtubule expression and network density decline with cardiac maturation. Overexpression of YAP5SA, a constitutively active YAP mutant, promotes microtubule growth by stabilizing microtubule dynamics, leading to CM dedifferentiation, cell cycle re-entry, and sarcomere disassembly. In contrast, colchicine blocks these processes and significantly attenuates YAP-induced cardiac regeneration. Live imaging reveals a distinct mode of sarcomere disassembly driven by enhanced microtubule polymerization, wherein microtubule plus-ends directly interact with α-actinin and displace α-actinin fragments, thereby facilitating sarcomere breakdown. Furthermore, the YAP5SA-S94A mutation, which disrupts the YAP and TEA domain interaction, significantly reduces YAP5SA-induced microtubule growth, sarcomere disassembly, and cell cycle activity. Mechanistically, cleavage under targets and release using nuclease combined with RNA sequencing identified direct YAP targets, including Ajuba and Tuba1b, which are critical for microtubule growth. CM-specific knockdown of Tuba1b attenuates YAP-driven sarcomere disassembly. CONCLUSIONS: These findings identify microtubule networks as an essential regulator modulating CM dedifferentiation and sarcomere reorganization, which is critical for CM cytokinesis and cardiac regenerative repair.

Animals↗
PubMed1979

The effects of calcium deprivation upon mechanical and electrophysiological parameters in skeletal muscle fibres of the frog.

1. The effects of Ca2+ deprivation upon mechanical and electrophysiological parameters of single muscle fibres from the m. semitendinosus and the m. iliofibularis of the frog were investigated. 2. When the external free Ca concentration was reduced in steps of one order of magnitude from 10(-3) to 10(-9) M, using up to 10 mM-EGTA and in the presence of 3 mM-Mg2+, the maximum force of K contractures declined by 5-15%, the plateau of maximum force shortened, and in most cases the phase of spontaneous relaxation lengthened. 3. In Ringer solution containing 10(-9) M-Ca2+ and 1 mM-Mg2+ 85% of maximum tetanic force could be maintained for at least 15 sec (5 Hz; 3 degrees C). 4. The reduction of external Ca2+ from 10(-3) to 10(-9) M and its replacement by Mg2+ induced a 20-30 mV shift towards more negative potentials of the 'steady state' inactivation curve (which relates maximum force upon full depolarization to the logarithm of the K concentration or the corresponding membrane potential during the conditioning period). 5. The same alteration in concentrations of divalent cations caused little or no change in the shape and potential dependence of the activation curve (which relates maximum force to the logarithm of the external K concentration of the corresponding membrane potential). 6. The threshold potential for the onset of delayed rectification (point voltage clamp) and that for the initiation of an action potential did not change when external Ca2+ was reduced to 10(-9) M and replaced by Mg2+. 7. When the concentration of EGTA2- was increased to 80 mM (in the presence of 5 mM-Mg2+) twitch height dropped to very small values within a few minutes. However, tetanic force (50 Hz) reaching 20-85% of the original value could still be induced after 1 hr in high EGTA2-. 8. The experiments show that external Ca2+ acts upon excitation-contraction coupling mainly by impeding 'inactivation'. A hypothesis is proposed in which the plateau of maximum force during a contracture is the consequence of a regenerative Cai2+-dependent shift of the inactivation curve towards more positive potentials.

Animals↗