A geroscience motivated approach to treat Alzheimer's disease: Senolytics move to clinical trials

Mech Ageing Dev. 2021 Dec:200:111589. doi: 10.1016/j.mad.2021.111589. Epub 2021 Oct 21.


The pathogenic processes driving Alzheimer's disease (AD) are complex. An incomplete understanding of underlying disease mechanisms has presented insurmountable obstacles for developing effective disease-modifying therapies. Advanced chronological age is the greatest risk factor for developing AD. Intervening on biological aging may alter disease progression and represents a novel, complementary approach to current strategies. Toward this end, cellular senescence has emerged as a promising target. This complex stress response harbors damaged cells in a cell cycle arrested, apoptosis-resistant cell state. Senescent cells accumulate with age where they notoriously secrete molecules that contribute to chronic tissue dysfunction and disease. Thus, benefits of cell survival in a senescent fate are countered by their toxic secretome. The removal of senescent cells improves brain structure and function in rodent models at risk of developing AD, and in those with advanced Aβ and tau pathology. The present review describes the path to translating this promising treatment strategy to AD clinical trials. We review evidence for senescent cell accumulation in the human brain, considerations and strategies for senescence-targeting trials specific to AD, approaches to detect senescent brain cells in biofluids, and summarize the goals of the first senolytic trials for the treatment of AD (NCT04063124 and NCT04685590). This article is part of the Special Issue - Senolytics - Edited by Joao Passos and Diana Jurk.

Keywords: Alzheimer’s disease; Biology of aging; Brain; Cellular senescence; Clinical trials; Exosomes; Geroscience; Neurodegeneration; Senolytics; Tauopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aging* / drug effects
  • Aging* / physiology
  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / physiopathology
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Cellular Senescence / drug effects
  • Clinical Trials as Topic
  • Disease Models, Animal
  • Humans
  • Senotherapeutics / pharmacology*


  • Senotherapeutics

Associated data

  • ClinicalTrials.gov/NCT04063124
  • ClinicalTrials.gov/NCT04685590