Complete Roadmap of Aging Therapies From Senolytics to AI-Driven Precision Medicine
A landmark review maps every major anti-aging strategy — senolytics, senomorphics, epigenetic reprogramming, and metabolic mimetics — with clinical trial data.
Summary
This comprehensive review published in Signal Transduction and Targeted Therapy systematically maps the biological hallmarks of aging and the therapeutic strategies designed to counter them. The authors cover three core intervention categories: senolytics (drugs that eliminate senescent cells, such as dasatinib plus quercetin), senomorphics (drugs that suppress the harmful secretions of senescent cells, such as rapamycin and metformin), and senoreversion (epigenetic reprogramming strategies that rejuvenate cells). Metabolic interventions including caloric restriction mimetics — spermidine, alpha-ketoglutarate, and ergothioneine — are shown to extend lifespan and improve healthspan in preclinical models. The review also highlights how artificial intelligence is accelerating discovery by integrating multiomics data and personalizing interventions. Clinical trials in idiopathic pulmonary fibrosis, Alzheimer's disease, and diabetic macular edema demonstrate early translational progress.
Detailed Summary
Aging is the single greatest risk factor for cancer, neurodegeneration, cardiovascular disease, metabolic syndrome, and autoimmune disease. With the global population aged 60 and above projected to double to 2.1 billion by 2050, and China's elderly population expected to reach 28% by 2040, the pressure on public health systems is immense. This review, authored by researchers from the National University of Singapore, Nutrilite Health Institute, and the Chinese Academy of Agricultural Sciences, constructs an integrated framework connecting aging mechanisms to therapeutic applications across a wide disease spectrum.
The authors organize aging around the now-canonical 12 hallmarks — genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis — plus newly identified hallmarks including immunoglobulin-associated senescence and endogenous retrovirus reactivation. These are categorized as primary (direct damage drivers), antagonistic (initially protective but ultimately harmful), and integrative (systemic compensatory failures). Understanding how these hallmarks interact determines the pace of aging and disease onset.
Three therapeutic strategies receive the most detailed treatment. Senolytics selectively eliminate senescent cells; dasatinib plus quercetin (D+Q), first proposed by the Kirkland group at Mayo Clinic in 2015, has advanced to clinical trials for idiopathic pulmonary fibrosis (2018), Alzheimer's disease (2023–2025), and diabetic macular edema (2024). Additional senolytics including ABT263, fisetin, and the BCL-xL/BCL-2 PROTAC degrader 753b are also reviewed. Senolytic CAR-T-cell therapy, proposed in 2020, offers a precision immunological approach. Senomorphics suppress the senescence-associated secretory phenotype (SASP), with rapamycin and metformin as the leading agents. The review traces the SASP concept to Campisi's group in 2008 and details downstream inflammatory signaling (NF-κB, IL-6, TNF-α) as intervention targets.
Senoreversion — rejuvenating rather than killing senescent cells — is highlighted as a frontier strategy. Partial in vivo reprogramming using Yamanaka factors (OSKM: Oct4, Sox2, Klf4, cMyc), first demonstrated to extend progeroid mouse lifespan in 2016, has been advanced by Altos Laboratories researchers who showed epigenetic age reversal without full dedifferentiation. In 2025, Ji's team from the Henan Academy of Sciences published the first direct demonstration that cellular senescence can be pharmacologically reversed. Metabolic interventions including spermidine, alpha-ketoglutarate (AKG), and ergothioneine activate autophagy, enhance mitochondrial biogenesis, and reprogram energy metabolism, with lifespan extension confirmed in multiple preclinical species. Clinically established drugs — metformin, GLP-1 receptor agonists, and lithocholic acid — are discussed for their mechanistic overlap with geroprotection.
A dedicated section addresses how artificial intelligence is transforming aging therapeutics. AI tools integrate multiomics datasets (genomics, proteomics, metabolomics, epigenomics) to identify novel biomarkers, predict drug candidates, design combination therapies, and enable personalized intervention protocols. The review closes by acknowledging persistent challenges: target specificity across tissue types, off-target toxicity of senolytics (particularly thrombocytopenia risk with ABT263), the paucity of long-term human safety data, and the difficulty of translating animal lifespan findings to human healthspan. The authors argue that convergence of AI, multitarget pharmacology, and precision medicine represents the most promising path to extending healthy human lifespan.
Key Findings
- Global population aged 60+ projected to reach 2.1 billion by 2050; China's elderly share expected to hit 28% by 2040, driving urgent need for anti-aging therapeutics
- Dasatinib + quercetin senolytic combination has reached clinical trials for idiopathic pulmonary fibrosis (2018), Alzheimer's disease (2023–2025), and diabetic macular edema (2024)
- Partial in vivo OSKM reprogramming extended lifespan in progeroid mice (2016) and reversed epigenetic aging signatures without full cellular dedifferentiation in subsequent studies
- In 2025, Ji's team (Henan Academy of Sciences) published the first direct experimental evidence that cellular senescence is pharmacologically reversible via senoreversion strategy
- Caloric restriction mimetics — spermidine, alpha-ketoglutarate, ergothioneine — demonstrated lifespan extension and healthspan improvement across multiple preclinical model organisms
- Two novel aging hallmarks identified: immunoglobulin-associated senescence (IgG accumulation) and endogenous retrovirus reactivation, expanding the canonical 12-hallmark framework
- Senolytic CAR-T-cell therapy (proposed 2020) demonstrated selective elimination of senescent cells with strong efficacy signals in aging-related disease models
Methodology
This is a narrative review article, not a primary clinical trial or meta-analysis. The authors systematically surveyed the published literature on aging hallmarks, mechanisms, and therapeutic interventions across preclinical models and clinical trials, covering research from 1925 to 2025. No original experimental data or statistical analyses were generated; findings are synthesized qualitatively from cited studies. Several authors are affiliated with Nutrilite Health Institute (Amway), which represents a potential commercial conflict of interest in sections covering nutritional supplements.
Study Limitations
As a narrative review, the paper does not perform systematic literature searches or meta-analytic pooling, limiting quantitative synthesis of effect sizes. The majority of lifespan extension data comes from preclinical models (mice, C. elegans, Drosophila), and human clinical trial evidence remains sparse and early-stage. Commercial affiliations with Nutrilite/Amway among co-authors may introduce bias in the coverage and framing of nutraceutical interventions.
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