TABLE 2.

Summary of immunosenescence interventions that may genoprotective.

Intervention	Evidence for beneficial effect on immunosenescence	Proposed mechanism(s) of action	Evidence for drug genoprotection	Effective dose
				In vitro	In vivo (human)
Spermidine	Improved vaccine-induced HCV- and RSV- specific responses in CD8+ T cells from old people Alsaleh et al. (2020)	Enhances hypusination of eIF5A and translation of TFEB, leading to induction of autophagy-related gene expression Zhang et al. (2019)	Promoted DSB repair by homologous recombination in U-2 OS cells Lee et al. (2019)	0.01–0.5 mM Puleston et al. (2014), Lee et al. (2019), Alsaleh et al. (2020)	1.2 mg/day Schwarz et al. (2018), though higher doses (15 mg/day) can be tolerated Senekowitsch et al. (2023)
	Improved flu-specific immune memory in old mice Puleston et al. (2014)	Increases autophagy in B cells and T cells from old individuals Zhang et al. (2019), Alsaleh et al. (2020)
Metformin	Improved survival (in women) from COVID-19 (Bramante et al., 2021) and other studies, reviewed in Justice et al. (2021)	Multiple targets, many of which act through AMPK activation Kulkarni et al. (2020)	Elicited pseudo-DDR in cancer cells Vazquez-Martin et al. (2011)	5 mM Vazquez-Martin et al. (2011), Lee et al. (2016)	500 mg twice daily, then increased to 2,000 mg daily at the end of 2 weeks led to average plasma concentration 18 μM metformin Kulkarni et al. (2018)
			Decreased %γH2AX+ and %8-oxo-dG+ intestinal stem cells in aged or paraquat-treated Drosophila Na et al. (2013)
mTOR inhibition	6-week pre-treatment with RAD001 vs. placebo prior to influenza vaccination increased antibody titre and decreased %PD-1+ T cells Mannick et al. (2014)	Decreases %PD-1+ T cells Mannick et al. (2014)	Attenuated immunosenescence effects of immune cell DNA damage in Vav-iCre +/− ;Ercc1 -/fl mice Yousefzadeh et al. (2021b)	0.01–1 µM Saha et al. (2014), Dominick et al. (2017), Yang et al. (2022)	Rapalogues RTB101 at 10 mg/day or combined RTB101 10 mg/day + RAD001 0.1 mg/day both beneficial Mannick et al. (2018)
			Dietary restriction (which restricts mTOR activation) prolonged life in DNA repairdeficient mice Vermeij et al. (2016)
	6-week dual BEZ235/RAD001 vs. placebo treatment in old people increased influenza antibody titre and decreased respiratory tract infections 1 year later Mannick et al. (2018)	Increases type I interferon antiviral gene expression Mannick et al. (2018)	Rapamycin treatment decreased # 53BP1 foci in WRN-deficient fibroblasts Saha et al. (2014)		1 mg/day rapamycin in older adults (average peak blood rapamycin concentration 7.88 nM (range 5.14–12.91)) Kraig et al. (2018)
			Rapamycin increased post-translational expression of DNA repair enzymes NDRG1 and MGMT Dominick et al. (2017)
p38 MAPK inhibitors	Improved response to VZV challenge in skin in old people Vukmanovic-Stejic et al. (2018), Chambers et al. (2021a)	Improves efferocytosis of macrophages promoting immune resolution after blister challenge De Maeyer et al. (2020)	Restored telomerase expression and reduced reactive oxygen species in senescent T cells Henson et al. (2014)	3 µM losmapimod De Maeyer et al. (2020), Chambers et al. (2021a)	15 mg twice daily losmapimod De Maeyer et al. (2020), Chambers et al. (2021a)
				500 nM BIRB 796 Henson et al. (2014)
		Decreases CCL2 expression from skin to decrease inflammatory monocyte recruitment to allow adaptive T cell response Chambers et al. (2021a)	Restored young morphology and proliferation in senescent DNA repair-deficient Werner syndrome fibroblasts Davis et al. (2005)	10 µM SB203580 Davis et al. (2005)
Vitamin D3	14-week vitamin D3 supplementation improved cutaneous response to VZV challenge in old people Chambers et al. (2021b)	Decreases inflammatory monocyte recruitment to site of challenge and allowed resident memory T cell adaptive response Chambers et al. (2021b)	1,25(OH)2 treatment increased recruitment of DNA repair factors to DNA lesions after ionising radiation in human fibroblasts Graziano et al. (2016)	100 nM Graziano et al. (2016), Elkafas et al. (2020)	6400 IU of vitamin D3 per day for 14 weeks; average serum concentration of 25(OH)D after supplementation was ∼125 nM
			Vitamin D3 upregulated DNA sensors and effectors and diminished DNA damage in myometrial stem cells isolated from rats developmentally treated with diethylstilbestrol Elkafas et al. (2020)
Nicotinamide riboside	Not yet assessed	Restores NAD+ levels that naturally decline with age Fang et al. (2019)	NR enhanced SIRT1-mediated deacetylation of Ku70 in the DNA-PK complex to promote NHEJ-mediated repair of DSBs in ATM-insufficient human neuroblastoma cells Fang et al. (2016)	0.5–1 mM NR Fang et al. (2016), Fang et al. (2019)	500 mg of NR twice daily for 6 weeks increased PBMC concentration of NAD+ by 60% compared to placebo; median NAD+ levels from 7.7 to 12.2 pmol/mg protein Martens et al. (2018) 1 g/day NR for 21 days increased blood NAD+ by > 2-fold (47.75 μM supplementation versus placebo 20.90 μM) Elhassan et al. (2019)
		Activates SIRT1 to promote mitophagy Fang et al. (2019)	NR promoted RAD51-mediated HR repair of DSBs Fang et al. (2019) NR supplementation in aged mice decreased %γH2AX+ muscle stem cells Zhang et al. (2016)
Enoxacin	Not yet assessed	Increases activity of RNAi machinery, DICER; promotes the generation of non-coding RNAs recruited to sites of DNA damage (DDRNAs) Gioia et al. (2019)	Treatment of HeLa cells prior to ionising radiation increased accumulation of 53BP1 foci at DNA lesions and decreased tail moment in neutral comet assay (readout for DSBs) Gioia et al. (2019)	50 µM Gioia et al. (2019)	400 mg twice daily enoxacin increased average plasma drug concentrations of 15.86 µM (SD 3.53, range 10.26–24.06 µM) Hamel et al. (2000)
				C. elegans lifespan extension when grown on plates supplemented with 100 μg/mL (312.19 µM) enoxacin Pinto et al. (2018)