Vincenzo Sorrentino

Aging is a complex biological process characterized by progressive functional decline, driving the incidence of age-related diseases such as neurodegeneration, metabolic disorders, and cardiovascular diseases. Therapeutic strategies targeting aging hallmarks can delay aging and mitigate disease risk. Emerging interventions focus on modulating core aging mechanisms, including cellular senescence, metabolic dysfunction, epigenetic alterations, and mitochondrial impairment, etc. Recent advances have focused on three strategies: senolytics (eliminating senescent cells, e.g., dasatinib + quercetin), senomorphics (inhibiting the senescence-associated secretory phenotype, e.g., rapamycin), and senoreversion (rejuvenating senescent cells via epigenetic reprogramming). Additionally, metabolic interventions such as caloric restriction mimetics (e.g., spermidine, α-ketoglutarate, ergothioneine) enhance mitochondrial function, activate autophagy, and reprogram energy metabolism, demonstrating lifespan extension and healthspan improvement in preclinical models. Collectively, these approaches hold promise for delaying aging and alleviating age-related pathologies, facilitating the transition to precision longevity medicine. Concurrently, artificial intelligence (AI) accelerates discovery by integrating multiomics data, predicting candidate compounds, identifying biomarkers, and enabling personalized interventions. Despite advancements, challenges remain in target specificity, off-target effects, and clinical translation. The convergence of AI, multitarget strategies, and precision medicine signals a transformative era in extending healthspan and combating aging-associated diseases. This review systematically summarizes current breakthroughs, clinical landscapes, and future directions in aging therapeutics, underscoring interdisciplinary strategies to redefine healthy aging.

Nicotinamide adenine dinucleotide (NAD⁺) is a coenzyme involved in a plethora of physiological reactions, with a key relevance in supporting mitochondrial function. Due to its critical role in these cellular processes, declining levels of NAD⁺ are associated with general aging and chronic disorders, including cognitive decline, sarcopenia, and metabolic diseases. These conditions are also typified by loss of mitochondrial health through dysfunction of homeostatic components such as mitophagy, unfolded protein response, and the antioxidant system. Therefore, raising cellular NAD⁺ through vitamin B3 family precursors or via drug-based interventions has become a broadly used strategy to restore mitochondrial and organismal homeostasis, with NAD⁺ precursors becoming a popular supplementation approach. As increasing components of the NAD⁺ biology are unraveled, this comprehensive review summarizes the advances in mechanisms of NAD⁺ metabolism and its modulation via compound-based strategies. Furthermore, it highlights the role of NAD⁺ in mitochondrial homeostasis in aging and disease conditions, the latest results of NAD⁺-boosting therapeutics in clinical trials, and areas of further translational development.

Chronic kidney disease (CKD) is a major global health issue, projected to become the fifth leading cause of mortality by 2040. Renal tubular cell senescence is a key driver of kidney fibrosis, the final manifestation of CKD. However, current treatment strategies, do not target senescent cells, as the underlying mechanisms driving this dysfunctional phenotype remain poorly described. Here, we identify nicotinamide-N-methyltransferase (NNMT), as a critical mediator of tubular senescence and fibrosis in CKD. Using human RNAseq profiles of CKD, we show that NNMT expression in the renal tubulointerstitium is strongly associated with CKD pathology and transcriptional signatures of cellular senescence. In human diabetic kidney disease biopsies, NNMT levels correlate with the senescence marker p21, kidney function decline, and fibrosis. Spatial transcriptomics further highlights that NNMT-positive tubules are senescent, fibrotic, and surrounded by a pro-inflammatory microenvironment. Preclinical models of early-stage CKD, show upregulation of NNMT and association with senescence. Overexpression of NNMT in TGF-β-stimulated tubular epithelial cells promotes senescence and partial epithelial-to-mesenchymal transition (EMT), while inhibition of NNMT in kidney cells and organoids is protective. Altogether, we identify NNMT as a novel therapeutic target in the early stages of CKD with the potential to reduce tubular senescence, fibrosis and significantly slow disease progression.

Aging is a complex and time-dependent decline in physiological function that affects most organisms, leading to increased risk of age-related diseases. Investigating the molecular underpinnings of aging is crucial to identify geroprotectors, precisely quantify biological age, and propose healthy longevity approaches. This review explores pathways that are currently being investigated as intervention targets and aging biomarkers spanning molecular, cellular, and systemic dimensions. Interventions that target these hallmarks may ameliorate the aging process, with some progressing to clinical trials. Biomarkers of these hallmarks are used to estimate biological aging and risk of aging-associated disease. Utilizing aging biomarkers, biological aging clocks can be constructed that predict a state of abnormal aging, age-related diseases, and increased mortality. Biological age estimation can therefore provide the basis for a fine-grained risk stratification by predicting all-cause mortality well ahead of the onset of specific diseases, thus offering a window for intervention. Yet, despite technological advancements, challenges persist due to individual variability and the dynamic nature of these biomarkers. Addressing this requires longitudinal studies for robust biomarker identification. Overall, utilizing the hallmarks of aging to discover new drug targets and develop new biomarkers opens new frontiers in medicine. Prospects involve multi-omics integration, machine learning, and personalized approaches for targeted interventions, promising a healthier aging population.

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD⁺) levels are hallmarks of skeletal muscle ageing and sarcopenia^1–3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid⁴, NAD⁺ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD⁺ pool and increases NAD⁺ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss–Handler pathway^5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD⁺-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD⁺-boosting strategy with therapeutic potential for age-associated muscle decline.

Editorial: Mitochondria at the nexus of metabolism, aging, and disease

Premature aging causes morphological and functional changes in the kidney, leading to chronic kidney disease (CKD). CKD is a global public health issue with far-reaching consequences, including cardio-vascular complications, increased frailty, shortened lifespan and a heightened risk of kidney failure. Dialysis or transplantation are lifesaving therapies, but they can also be debilitating. Currently, no cure is available for CKD, despite ongoing efforts to identify clinical biomarkers of premature renal aging and molecular pathways of disease progression. Kidney proximal tubular epithelial cells (PTECs) have high energy demand, and disruption of their energy homeostasis has been linked to the progression of kidney disease. Consequently, metabolic reprogramming of PTECs is gaining interest as a therapeutic tool. Preclinical and clinical evidence is emerging that NAD⁺ homeostasis, crucial for PTECs’ oxidative metabolism, is impaired in CKD, and administration of dietary NAD⁺ precursors could have a prophylactic role against age-related kidney disease. This review describes the biology of NAD⁺ in the kidney, including its precursors and cellular roles, and discusses the importance of NAD⁺ homeostasis for renal health. Furthermore, we provide a comprehensive summary of preclinical and clinical studies aimed at increasing NAD⁺ levels in premature renal aging and CKD.