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Introduction <p>Alzheimer’s disease affects approximately 55 million people globally, accounting for 60–70% of all dementias. Cellular senescence—characterized by irreversible cell cycle arrest and release of pro-inflammatory mediators through the SASP—has been proposed as a contributing mechanism in AD pathogenesis. Senolytics (dasatinib, quercetin, fisetin) and senomorphics (rapamycin, metformin) represent emerging therapeutic strategies targeting this pathway.</p> Objective <p>To systematically evaluate the efficacy, safety, and biomarker profiles of senolytic and senomorphic therapies in Alzheimer’s disease and assess the methodological quality of available evidence.</p> Methodology <p>Systematic search in PubMed, Scopus, Cochrane, and ClinicalTrials.gov (2020–2025), following PRISMA 2020. Risk of bias assessed with ROBINS-I and SYRCLE; certainty of evidence with GRADE. PROSPERO: CRD420251132734.</p> Results <p>From 200 records, 12 studies were included (4 preclinical, 5 pilot clinical trials, 1 phase I trial, 2 registered protocols without results). Dasatinib was detectable in CSF in 4 of 5 participants in one pharmacokinetic study; quercetin and rapamycin were undetectable in CSF across all studies. Modulation of surrogate biomarkers (TNF-α, IL-6, p16, p21, GFAP, phosphorylated tau-181) was observed but was not consistently directional across agents. Short-term safety data showed high adherence and predominantly mild adverse events. Certainty of evidence was rated low to very low for all outcomes.</p> Conclusions <p>Available evidence is insufficient to establish the efficacy of senolytic or senomorphic therapies in AD. Observed biomarker changes are exploratory surrogate outcomes and do not indicate clinical benefit. Randomized placebo-controlled trials with validated clinical endpoints are required.</p>

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Systematic review of cellular senescence as a therapeutic target in Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月13日

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  • Dennis Monzerrat Lopez Samayoa,
  • Karina Consuelo Moreno Rodríguez,
  • Lilith Michelle Salazar Rubio,
  • Denisse Alejandra Mercado Morales,
  • Thaily Marlene Ramírez Reyes,
  • Natalia Daneli Valdez Montano,
  • Ángel Rafael Martínez Serrato,
  • Nina Mendez Dominguez

摘要

Introduction

Alzheimer’s disease affects approximately 55 million people globally, accounting for 60–70% of all dementias. Cellular senescence—characterized by irreversible cell cycle arrest and release of pro-inflammatory mediators through the SASP—has been proposed as a contributing mechanism in AD pathogenesis. Senolytics (dasatinib, quercetin, fisetin) and senomorphics (rapamycin, metformin) represent emerging therapeutic strategies targeting this pathway.

Objective

To systematically evaluate the efficacy, safety, and biomarker profiles of senolytic and senomorphic therapies in Alzheimer’s disease and assess the methodological quality of available evidence.

Methodology

Systematic search in PubMed, Scopus, Cochrane, and ClinicalTrials.gov (2020–2025), following PRISMA 2020. Risk of bias assessed with ROBINS-I and SYRCLE; certainty of evidence with GRADE. PROSPERO: CRD420251132734.

Results

From 200 records, 12 studies were included (4 preclinical, 5 pilot clinical trials, 1 phase I trial, 2 registered protocols without results). Dasatinib was detectable in CSF in 4 of 5 participants in one pharmacokinetic study; quercetin and rapamycin were undetectable in CSF across all studies. Modulation of surrogate biomarkers (TNF-α, IL-6, p16, p21, GFAP, phosphorylated tau-181) was observed but was not consistently directional across agents. Short-term safety data showed high adherence and predominantly mild adverse events. Certainty of evidence was rated low to very low for all outcomes.

Conclusions

Available evidence is insufficient to establish the efficacy of senolytic or senomorphic therapies in AD. Observed biomarker changes are exploratory surrogate outcomes and do not indicate clinical benefit. Randomized placebo-controlled trials with validated clinical endpoints are required.