TABLE 1.

Heart Failure Trials Targeting Select Hallmarks of Aging Biology

Hallmark of Aging	Therapeutic Interventions/Target	Impact
Impaired proteostasis/ autophagy	• Tafamidis (transthyretin [TTR] stabilizer) • Acoramidis (TTR stabilizer) • Patisiran (TTR silencer) • NTLA-2001 (TTR gene editing)a • ALXN-2220 (formerly NI006) (TTR clearance antibody) • Spermidine (autophagy)a	• ↓ CV hospitalizations, ↓ mortality, slows decline in functional capacity and QoL (ATTR-CA) • ↓ CV hospitalizations, ↓ all-cause mortality, attenuates rise in NT-proBNP, slows decline in 6MWT (ATTR-CA) • Preserves functional capacity and QoL, stablized cardiac function (ATTR-CA) • NCT06183931 (ATTR-CA) • ↓ ECV, ↓ cardiac tracer uptake on scintigraphy, ↓ NT-proBNP (ATTR-CA) • NCT05128331 (HFpEF)
Mitochondrial dysfunction	• Coenzyme Q10 • Alpha lipoic acid • Nicotinamide riboside (NAD+)a • Elamipretide • Perhexiline (CPT) • PUFA • Ketone estera	• ↓ CV hospitalizations, ↓ mortality, NC/↑ LVEF, NC/↑ 6MWT, NC/↑ NYHA (HFrEF); NC diastolic function, NC NT-proBNP (HFpEF) • ↓ Troponin, ↓ inflammation, ↑ peak systolic strain (diabetic CMP) • ↓ Inflammation, NCT04528004 (HFrEF) • NC LVEF, NC LVESV (HFrEF); NCT02814097 (HFpEF) • NC/↑ LVEF, ↑ NYHA, ↑ QoL, ↑ exercise capacity (HFrEF) • ↓ CV hospitalizations, ↓ mortality, ↑ LVEF (HFrEF/HFpEF) • NCT05348460 (HFrEF)
Deregulated nutrient sensing	• Rapamycin (mTOR)a • Metformin (AMPK)a	• ↑ Physical function; NCT04996719 (HFpEF) • NC LVEF, exercise capacity (HFrEF); NCT05093959 (HFpEF)
Inflammation	• Canakinumab (IL-1β) • Anakinra (IL-1) • Colchicine (tubulin)a • Methotrexate (multiple) • Infliximab (TNFα)	• ↓ HHF, ↓ HF-related mortality (iCMP) • ↓ NT-proBNP, ↑ exercise capacity (<4 wks), NC exercise capacity (>12 weeks), NC HHF, NC mortality (HFrEF and HFpEF) • NC NYHA, NC HHF, NC mortality; NCT05637398 (HFpEF) • NC HHF, NC 6MWT, NC QoL (iCMP) • NC HHF, NC mortality; [ mortality (with higher doses) (HFrEF)
Altered intercellular communication	• Pirfenidone (fibrosis)a • Allogenic derived cells (fibrosis)a	• NCT02932566 (HFpEF) • NCT02941705 (HFpEF)
Telomere shortening	• AAV9-cTnT-modTERT (telomerase)a	• NCT05837143 (HFrEF)
Epigenetic alterations	• CDR132L (miR-132 inhibitor) a • TN-301 (HDAC6)	• ↓ NT-proBNP, NCT05350969 (HFrEF/iCMP); NCT05953831 (HFpEF) HFpEF
Cellular senescence	• Fisetina	• NCT06133634, NCT03675724 (assessing vascular function, frailty, inflammation in older adults; HF not excluded)
Dysbiosis	• Rifaxamin, Saccharomyces boulardiia • Empagliflozin a • Ensure Immunonutrition Shakea • Lactobacillus plantaruma • Acacia gum	• NCT02637167 (HFrEF) • NCT05584319 (HFpEF) • NCT05655910 (HFrEF) • NCT05752760 (HFpEF/HFrEF) • NCT03409926 (HFpEF/HFrEF)
Stem cell exhaustion	• Mesenchymal stromal cells • BM-MNC (with or without G-CSF) • C-kit+ cardiac cells • CD34+ cells	• NC/↓ HHF, NC/↓ cardiacdeath, NC/↑ QoL, ↑ 6MWT, NC/↓ LVEDV, NC/↑ LVEF, (HFrEF) • NC/↑ LVEF, functional capacity, NYHA, QoL (HFrEF) • ↓ HHF, NC exercise capacity, NC 6MWT, NC LVEF, NC LV volumes, NC NT-proBNP, • ↓ Mortality, ↑ LVEF, NC LV volumes, ↑ 6MWT, ↓ NT-proBNP (HFrEF)

^aActive clinical trial.

6MWT = 6-minute walk time; AMPK = AMK-activated protein kinase; ATTR-CA = transthyretin cardiac amyloidosis; BM-MNC = bone marrow-derived mononuclear cells; CPT = carnitine palmitoyltransferase; CV = cardiovascular; ECV = extracellular volume; G-CSF = granulocyte colony stimulating factor; HDAC6 = histone deacetylase 6; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; HHF = hospitalizations for heart failure; iCMP = ischemic cardiomyopathy; IL = interleukin; LV = left ventricular; LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; mTOR = mechanistic target of rapamycin; NAD⁺ = nicotinamide adenine dinucleotide; NC = no change; NT-proBNP = N-terminal pro-B-type natriuretic peptide; PUFA = polyunsaturated fatty acid; QoL = quality of life; TNF = tumor necrosis factor.