TABLE 1.

Defined molecular targets that delay aging by acting on the mitochondria-proteostasis axis.

Mechanism	Target	Intervention	Organism/system	Outcome	References
Upstream activation of autophagy	↑ AMPK	- Salicylates - Metformin	- C. elegans - Mice	Lifespan and healthspan extension	Martin-Montalvo et al., 2013; Shamalnasab et al., 2018; Bharath et al., 2020
	↓ Insulin/IGF-1	- Genetic mutation (daf-2) - Diazoxide	- C. elegans - Rats	Lifespan extension	Melendez, 2003; Tóth et al., 2008; Meng et al., 2018
	↑ SIRT1	- Resveratrol - NAD+ precursors	- C. elegans - Mice	- Lifespan extension - Delayed cardiac aging	Barger et al., 2008; Morselli et al., 2010a, b; Abdellatif et al., 2021
	↓ mTORC1	- Rapamycin	- C. elegans - Drosophila - Mice	Lifespan extension	Bjedov et al., 2010; Robida-Stubbs et al., 2012; Neff et al., 2013
Direct activation of autophagy machinery proteins	↑ ULK1	- BL-918 molecule	- Mice	Neuroprotection	Ouyang et al., 2018
	↑ Beclin 1	- Genetic mutation (Beclin 1F121A) - Tat-Beclin 1 peptide	- Mice	- Extension of lifespan and healthspan (↓ renal, cardiac and oncological pathologies) - Ameliorated cardiac and memory performance	Shirakabe et al., 2016; Fernández et al., 2018; Sun et al., 2018; Glatigny et al., 2019
Lysosomal clearance of autophagic cargo	↑ TFEB	- Genetic overexpression (HLH-30) - Small-molecule TFEB activators - Trehalose	- C. elegans - Mice	- Lifespan extension - Hepatoprotection - Attenuated vascular aging	LaRocca et al., 2012; Lapierre et al., 2013; Wang et al., 2017
Mitochondrial biogenesis	↑ PGC-1α	- PPARγ agonists (GW1929) - Cell-specific genetic overexpression	- Human dopaminergic neurons - Mice (skeletal myocytes) - Mice (cardiomyocytes)	- Neuroprotection - Extension of median lifespan in females and maximal lifespan in males and enhanced endurance capacity and protection from age-related sarcopenia, but aggravated age-related bone loss - Accentuated cardiac aging and shorter lifespan with higher overexpression, but cardioprotection with moderate overexpression	Mäkelä et al., 2016; Garcia et al., 2018; Whitehead et al., 2018; Zhu et al., 2019; Yang S. et al., 2020
Mitochondrial fission	↑ DRP1	- Genetic upregulation - Mitochondrial division inhibitor-1	- Drosophila (midlife) - Mice (skeletal muscle) - Mice (intravenous injection)	- Lifespan and healthspan extension - Insulin resistance and impaired muscle development - Protection against cardiac ischemia-reperfusion injury	Ong et al., 2010; Jheng et al., 2012; Touvier et al., 2015; Rana et al., 2017
Mitochondrial respiration	↓ ETC	- Genetic disruption (Mit mutants) - Cytochrome c oxidase moderate inhibitor	- C. elegans - Mice	- Lifespan extension - Healthspan extension, including reduced visceral fat and enhanced glucose homeostasis	Rea et al., 2007; Tavallaie et al., 2020