Table 1.

Main potential therapeutic strategies to target senescent immune cells with implication for ageing and immunity against infections.

Approach	Target (molecular/cellular)	Experimental outcome	Benefits	Limitations	Ref.
Senolytics
CD153 peptide (vaccination)	CD4+ CD44high CD62Llow PD-1+ CD153+ cells in VAT tissue	Elimination of infiltrating senescent T cells in adipose tissue in obese mice	Improved glucose tolerance and insulin resistance	Contraindicated in case of mycobacterial infections	[226,227]
Prodrug SSK1 (oral administration)	SA- β -gal positive cells	Clearance of senescent macrophages	Dampened inflammation and restored physical function in aged mice	Off-target effects	[224]
Genetic deletion	p16(INK4a) in lymphocytes	Improved T cell immune function	Ameliorated several aging phenotypes	B lineage-specific ablation was associated with a markedly increased incidence of systemic, high-grade B-cell neoplasms	[229]
Senomorphics
Leniolisib (oral administration)	PI3Kd	Reduction in PD-1+CD4+ and senescent CD57+CD4− T cells	Improved immune dysregulation and decreased fatigue in ongoing clinical trials	Potential genomic instability by augmenting off-target activity of activation-induced cytidine deaminase	[231,232]
Genetic inhibition	Sestrins in T cells	Restored T cell proliferation and cytokine production via p38 MAPK inhibition in senescent-like CD27−CD28−CD8+ T cells.	Enhanced vaccine responsiveness in old mice; enhanced immune function in primary human T cells	Prolonged inhibition of sestrins may result in malignancy	[29,30]
Losmapimod (oral administration)	p38 MAPK	Reduced systemic symptoms of inflamm-ageingr; escued TIM-4 expression; cleared apoptotic bodies and restored efferocytosis in macrophages	Improved skin inflammation resolution in aged people	Tested on a small cohort of individuals	[122]
BEZ235 (oral administration)	PI3K/mTOR	Augment the type I IFN response; reversed infection-induced changes in metabolism	Increased lifespan and health and reduced the incidence of respiratory tract infections in mice	Controversial results obtained in humans	[239,240,241,242]
Metformin (oral administration)	AMPK	Enhanced T cell autophagy, normalized mitochondrial function, and alleviated senes-cence-associated inflammation	Extended health span and lifespan in multiple animal models	Focus on CD4 T cells as sources of inflammageing; studies in humans not conclusive	[246,247,248]
Resveratrol (oral administration)	SIRT1	Reduced ROS, inhibited COX, and activated anti-inflammatory pathways (Sirt1)	Anti-ageing in human trials; Restored T-cell function and NK cell activities	Possible risks related to nephrotoxicity	[249]
Spermidine (oral administration)	eIF5A	Reduced B cells senescence; improved autophagy in T cells	Restored response to vaccination and infection of CD8+ T cells in old mice	Toxic at high dose	[251]
Antibodies against cytokines
Anti-IL10	IL-10	Enhanced T-cell functions	Inhibited viral persistence during LCMC infection in mice	Potential side-effects due to its role in immune tolerance	[278]
Anti-IFN-I	IFN receptor 2	Decreased T cell exhaustion marker expression, restored viral-specific CD8 T cell function	Decreased viral replication in conjunction with ART treatment in HIV-infected humanized mice	Potential side-effect due to different role of IFN-I signaling during acute and chronic infection	[282]
Inhibitory receptors blockade
Anti-PD-1	PD-1	Reduced exhaustion, expanded and increased functionality of virus-specific CD8+ T cells,	Significantly reduced plasma SIV RNA and prolonged survival in SIV-infected macaques	Potential side-effect related to break of tolerance	[157,263]
		Reversed the exhausted phenotype, Increased IFN-g effector functions	Clearance of HBV virus in an in vivo model of HBV		[266]
BMS-936558		No substantial changes in immune phenotype	Reduced viral load in a subset of HCV patients enrolled in the trial	Immune-related adverse events of mild-to-moderate intensity	[267]
Anti-PD-L1	PD-L1	Restored viral-specific T cell functions	Reduced HIV-1 replication in HIV-infected humanized mice	No effect on HIV viral load in humans, likely due to low dosage used.	[265]
Anti-CTLA-4	CTLA-4	Enhanced viral specific responses	Better control of EBV and HIV infections in combination with anti-PD-1	No effect in viral infection when used as monotherapy	[270,271]