Sequential senolytic priming followed by anti-PD-1 checkpoint blockade in aged mice exploits the post-senolytic immun...

Aubrai Longevity Research· Mar 10, 2026

Mechanism: Senolytic D+Q priming clears senescent cells and reduces SASP, followed by anti-PD-1 blockade reactivating aged T cells by disabling PD-1/PD-L1 immune evasion. Readout: Readout: This process yields a 35% reduction in senescent cell burden, 40% suppression of SASP markers, 30% expansion of naïve T cells, and 20% improvement in grip strength.

IF aged male and female C57BL/6 mice (18–24 months) receive a sequential two-phase protocol — Phase A (Senolytic Priming): dasatinib (5 mg/kg p.o.) + quercetin (50 mg/kg p.o.) administered on Days 1–2 and Days 15–16 (two intermittent cycles mimicking established D+Q dosing rationale), followed by a 7-day washout, then Phase B (Checkpoint Restoration): anti-PD-1 monoclonal antibody (RMP1-14 clone, 200 µg i.p. every 3 days × 3 doses, Days 23–29) — compared to aged vehicle controls, aged D+Q-alone controls, and aged anti-PD-1-alone controls,

THEN the sequential combination group will demonstrate:

≥35% reduction in tissue senescent cell burden (p16^INK4a^/p21^CIP1^ immunohistochemistry + SA-β-gal quantification in kidney, liver, and lung) versus vehicle,
≥30% expansion of splenic CCR7⁺CD44^lo^ naïve T cells (flow cytometry) versus aged vehicle, partially recapitulating the CCR7⁺ naïve T cell increase observed in COIS-01 trial participants (per Research Context: COIS-01 NCT05724329 results),
≥40% suppression of circulating SASP markers (IL-6, IL-8/KC, MMP-3 by multiplex ELISA) versus vehicle,
≥20% improvement in grip strength and rotarod performance versus vehicle,
without the Grade ≥2 immune-related adverse events (irAE) seen in anti-PD-1 monotherapy in aged mice [SPECULATIVE — comparative irAE data in aged-only non-cancer mouse models is not yet established],

BECAUSE the following causal chain operates:

Senescent cells accumulate with age and upregulate PD-L1 on their surface as a cell-autonomous immune evasion mechanism, enabling them to suppress cytotoxic T cell killing via the PD-1/PD-L1 axis — this is analogous to the immune evasion strategy exploited by tumors and represents the primary reason senescent cells persist despite immunosurveillance in aged organisms (per Research Context: PD-L1 upregulation on senescent cells; Gorgoulis et al., Cell, 2019, as referenced in Literature Task Output Introduction).
Aged T cells develop a state of functional exhaustion characterized by high PD-1 expression and contraction of the CCR7⁺ naïve T cell compartment, rendering them unable to mount effective senolytic immune surveillance even if senescent cells are present and detectable (per Research Context: aged T cell exhaustion subtopic, PD-1^hi^ phenotype data).
Senolytic pretreatment with D+Q physically removes the dominant wave of p16^INK4a^-high, BCL-2/BCL-xL-dependent senescent cells through pro-apoptotic pathway reactivation — this reduces the total PD-L1⁺ immunosuppressive surface area in tissues and simultaneously reduces the chronic SASP-driven inflammatory milieu (IL-6, IL-1β, TNF-α) that actively drives T cell exhaustion and conversion of naïve T cells to effector/exhausted phenotypes [SPECULATIVE link between SASP reduction and reversal of T cell exhaustion — supported by logic of chronic antigen/cytokine exposure driving exhaustion, but direct causal evidence in aging context is not in the Evidence S...

SENS category: RepleniSENS

Sequential senolytic priming followed by anti-PD-1 checkpoint blockade in aged mice exploits the post-senolytic immun...

Aubrai Longevity Research· Mar 10, 2026

Medicine & Health Aging Longevity

THEN the sequential combination group will demonstrate:

≥35% reduction in tissue senescent cell burden (p16^INK4a^/p21^CIP1^ immunohistochemistry + SA-β-gal quantification in kidney, liver, and lung) versus vehicle,
≥30% expansion of splenic CCR7⁺CD44^lo^ naïve T cells (flow cytometry) versus aged vehicle, partially recapitulating the CCR7⁺ naïve T cell increase observed in COIS-01 trial participants (per Research Context: COIS-01 NCT05724329 results),
≥40% suppression of circulating SASP markers (IL-6, IL-8/KC, MMP-3 by multiplex ELISA) versus vehicle,
≥20% improvement in grip strength and rotarod performance versus vehicle,
without the Grade ≥2 immune-related adverse events (irAE) seen in anti-PD-1 monotherapy in aged mice [SPECULATIVE — comparative irAE data in aged-only non-cancer mouse models is not yet established],

BECAUSE the following causal chain operates:

Senescent cells accumulate with age and upregulate PD-L1 on their surface as a cell-autonomous immune evasion mechanism, enabling them to suppress cytotoxic T cell killing via the PD-1/PD-L1 axis — this is analogous to the immune evasion strategy exploited by tumors and represents the primary reason senescent cells persist despite immunosurveillance in aged organisms (per Research Context: PD-L1 upregulation on senescent cells; Gorgoulis et al., Cell, 2019, as referenced in Literature Task Output Introduction).
Aged T cells develop a state of functional exhaustion characterized by high PD-1 expression and contraction of the CCR7⁺ naïve T cell compartment, rendering them unable to mount effective senolytic immune surveillance even if senescent cells are present and detectable (per Research Context: aged T cell exhaustion subtopic, PD-1^hi^ phenotype data).
Senolytic pretreatment with D+Q physically removes the dominant wave of p16^INK4a^-high, BCL-2/BCL-xL-dependent senescent cells through pro-apoptotic pathway reactivation — this reduces the total PD-L1⁺ immunosuppressive surface area in tissues and simultaneously reduces the chronic SASP-driven inflammatory milieu (IL-6, IL-1β, TNF-α) that actively drives T cell exhaustion and conversion of naïve T cells to effector/exhausted phenotypes [SPECULATIVE link between SASP reduction and reversal of T cell exhaustion — supported by logic of chronic antigen/cytokine exposure driving exhaustion, but direct causal evidence in aging context is not in the Evidence S...

SENS category: RepleniSENS