Aging in Heart Failure

Abstract

Age is among the most potent risk factors for developing heart failure and is strongly associated with adverse outcomes. As the global population continues to age and the prevalence of heart failure rises, understanding the role of aging in the development and progression of this chronic disease is essential. Although chronologic age is on a fixed course, biological aging is more variable and potentially modifiable in patients with heart failure. This review describes the current knowledge on mechanisms of biological aging that contribute to the pathogenesis of heart failure. The discussion focuses on 3 hallmarks of aging—impaired proteostasis, mitochondrial dysfunction, and deregulated nutrient sensing—that are currently being targeted in therapeutic development for older adults with heart failure. In assessing existing and emerging therapeutic strategies, the review also enumerates the importance of incorporating geriatric conditions into the management of older adults with heart failure and in ongoing clinical trials.

Heart failure (HF), a heterogenous clinical syndrome of pulmonary or systemic congestion caused by a structural and/or functional abnormality in the heart, disproportionately affects older adults.¹ Age is among the most potent risk factors independently associated with HF, regardless of ejection fraction, and its outcomes. Although the passage of time allows for greater exposure to known causes of HF (eg, coronary artery disease), even in the absence of overt myocardial injury, the aging cardiovascular system mirrors many of the phenotypes in HF^2,3 (Central Illustration).⁴ This substrate places older adults at particularly high risk of developing HF, where even minor perturbations can shift this vulnerable homeostatic state toward the pathologic state of HF. Indeed, the risk of developing HF is ~20-fold higher among adults ≥60 years old, compared with their younger counterparts.⁵

CENTRAL ILLUSTRATION. Aging Processes in Heart Failure.

Physiological and biological aging of the cardiovascular system underlie the strong association between chronologic age and heart failure. This figure depicts the evolution of how “age” is being studied in heart failure and the shifting importance from chronologic to biological age in management of older adults with heart failure. The figure incorporates the updated hallmarks of aging outlined by Lopez-Otin et al⁹ and was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Although the association between chronologic age and HF risk is well established, our understanding of the mechanisms underlying this relationship remains incomplete, and this has limited therapeutic development in HF. This issue has implications on advancing care for the rapidly growing older adult population with HF, which notably includes an increasing number of septagenarians, octagenarians, and nonagenarians in the United States and beyond. In response to this knowledge gap, the National Institutes of Health launched a Geroscience Initiative in 2012 with the following goals: 1) elucidating how biological aging contributes to the pathogenesis of chronic diseases, such as HF, in older adults; and 2) harnessing this knowledge to develop new therapeutics to prevent or delay these diseases and slow the functional decline associated with age.⁶

Recent reviews have highlighted the emerging role of geroscience in the broader scope of cardiovascular disease (CVD).^7,8 Here we review how geroscience is providing new insights into HF pathophysiology and leading to the development of novel gerotherapeutic strategies for HF. Additionally, we enumerate an approach to incorporating geriatric conditions into the management of older adults with HF as a window into systemic biological age and emphasize the need to integrate geriatric conditions into clinical trials to assess the impact of established and emerging therapeutics.

BIOLOGICAL AGING: AN EMERGING THERAPEUTIC TARGET FOR HF

The distinction between chronologic and biological age is a core principle in geriatric medicine. Chronologic age is easy to recognize (age in years following birth) and progresses at a predictable rate. Biological age is more variable and is assessed by various metrics, including telomere length, epigenetic clocks, and clinical frailty phenotypes. The processes governing biological age are hypothesized to be common drivers of chronic disease pathogenesis in older adults. In other words, whereas chronologic age is on a fixed path, biological age is potentially modifiable. Thus, intervening on biological age could have broad implications on how we treat chronic diseases such as HF.

In accordance with this central geroscience concept, Lopez-Otin et al^4,9 published the first reports on the “hallmarks of aging,” where they described 12 fundamental biological processes that dictate organismal aging Although the study of aging is centuries old, this newer concept of “aging hallmarks” has provided a useful framework for investigating how mechanisms of biological aging contribute to HF (Central Illustration). Here we focus on 3 specific hallmarks of aging—impaired proteostasis, mitochondrial dysfunction, and deregulated nutrient sensing—in which emerging evidence supports a causal role in cardiac aging and HF and is leading to the translation of gerotherapeutics specifically in older adults with HF. It is important to emphasize that all 12 hallmarks of aging contribute to HF pathophysiology, and many of these hallmarks have been the topics of excellent reviews in cardiovascular aging.^10–16 Moreover, as highlighted by the Unitary Theory of Fundamental Aging Mechanisms, there are complex interactions and interdependence among these processes, whereby each hallmark can affect another, thereby making it unlikely that any single hallmark functions in isolation.¹⁷ Although reviewing all 12 hallmarks in depth is beyond the scope of this review, Table 1 provides an overview of recent and emerging clinical trials targeting the various hallmarks of aging in HF.

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.

IMPAIRED PROTEOSTASIS

BIOLOGY IN AGING AND DISEASE.

A universal hallmark of cellular aging is the decline in intracellular quality control systems. Proteostasis is the process by which cells regulate their protein content, which in humans consists of ~1 to 3 billion proteins per cell. When proteostasis is compromised, misfolded or aggregated proteins accumulate, leading to impairments in cellular function and survival. Given the greater impact of proteotoxicity in postmitotic cells, such as neurons and cardiomyocytes, the nervous and cardiovascular systems are disproportionately affected. Not surprisingly, loss of proteostasis contributes to the causal pathobiology in Alzheimer dementia¹⁸ and cardiac amyloidosis.¹⁹

Proteostasis is regulated by highly dynamic and complex intracellular machinery that encompasses molecular chaperones (eg, heat shock proteins) that facilitate proper folding and translocation of proteins, stress-responsive pathways such as the unfolded protein response (UPR), and proteolytic pathways such as the ubiquitin-proteasome (UPS) and autophagosome-lysosome systems. These components ultimately decide the fate of misfolded proteins and dictate whether they will be refolded or eliminated.

ROLE IN CARDIAC AGING AND HF.

With aging, impairments in all arms of the proteostasis network occur.²⁰ The best evidence for a causal role of this biology in cardiac aging and HF comes from cardiac-specific manipulation of this process in animal models. Inhibition of autophagy, UPS, or UPR in the heart is sufficient to induce HF in young animals, whereas restoring these processes, through either cardiomyocyte-specific genetic manipulation or pharmacologic activators (eg, spermidine), can reverse adverse myocardial remodeling and cardiac dysfunction in animal models of cardiac aging or HF with preserved ejection fraction (HFpEF).^21–24 Moreover, forced cardiac overexpression of preamyloid oligomers or mutated chaperones is sufficient to induce cardiac hypertrophy and HF in animal models of cardiac amyloidosis or desmin-related cardiomyopathy.^25,26 Age-associated defects in hepatic chaperone and UPR capacity also increase cardiac transthyretin (TTR) deposition,²⁷ and inhibiting cardiomyocyte autophagy accelerates intracellular protein aggregation, myocardial fibrosis, and cardiac dysfunction in animal models of desmin-related cardiomyopathy.²⁸ Taken together, these preclinical studies strongly implicate a causal role of impaired proteostasis in HF.

THERAPEUTIC DEVELOPMENT.

Targeting impaired proteostasis mechanisms in age-related HF syndromes has been a recent bench-to-bedside success story with pharmacologic agents now part of guideline-directed management for cardiac amyloidosis.^29,30 TTR stabilizers have garnered regulatory approval on the basis of successful phase III trials in TTR amyloid cardiomyopathy, the prototypical disease of impaired proteostasis that almost exclusively affects older adults. Data from these trials demonstrate robust and consistent effects of stabilizing TTR proteins with tafamidis and acoramidis, which reduce cardiovascular and overall hospitalizations.³⁰ More recently, RNA interference therapeutics that genetically inhibit TTR production in hepatocytes have shown that this approach can also stabilize this progressive and previously fatal form of HF.³¹ Phase III trials are also being initiated with an in vivo, systemically delivered, investigational CRISPR-based therapy designed to inactivate the TTR gene in liver cells and thereby prevent the production of TTR protein,³² whereas humanized monoclonal antibodies specifically targeting misfolded TTR have shown early evidence of efficacy in TTR cardiac amyloidosis.³³

MITOCHONDRIAL DYSFUNCTION

BIOLOGY IN AGING AND DISEASE.

Mitochondria are central regulators of cellular metabolism and energetics. They not only serve as the primary site for adenosine triphosphate (ATP) generation, but in doing so they also underlie the free radical theory of aging, which proposes that oxidative stress is responsible for the cumulative cellular damage that causes aging.³⁴ Although this theory has been somewhat controversial, oxidative stress from mitochondrial dysfunction is widely accepted as an important mechanism in age-related disorders, including dementia,³⁵ frailty/sarcopenia,³⁶ and HF.³⁷

Multiple factors contribute to age-associated mitochondrial dysfunction, including self-perpetuating oxidative damage, nicotinamide adenine dinucleotide (NAD⁺) depletion, reduced mitogenesis, impaired mitophagy, morphologic changes, and somatic mutations.^38,39 Mitochondria notably possess their own genome (mtDNA), and the accumulation of mtDNA mutations contributes to age-associated mitochondrial dysfunction. The PolG mutator mouse provides direct evidence for a causal role of mitochondrial dysfunction in aging. Defective mitochondrial DNA polymerase and ineffective mtDNA proofreading in these mice led to the accumulation of mtDNA mutations and oxidative stress and subsequently accelerated aging phenotypes in multiple organs, including the heart.^38,40,41

ROLE IN CARDIAC AGING AND HF.

With its high energy demands, the heart possesses the highest content of mitochondria among all organs. Mitochondria constitute ~30% of the total volume in cardiomyocytes and are responsible for generating >90% of the ATP used by the heart. In the aged heart, deleterious changes in mitochondrial morphology, membrane integrity, volume, and function all occur.^39,42 These changes are not only associated with increased reactive oxygen species (ROS)–mediated cellular damage and metabolic reprogramming (a shift from fatty acid [FA] oxidation to glycolytic metabolism), but they also intersect with other mechanisms of cardiac aging, including dysregulated calcium (Ca²⁺) cycling, proteostasis, metainflammation, and senescence.^37,39,43 Definitive evidence for a causal role of mitochondrial dysfunction and oxidative stress in cardiac aging comes from mice in which mitochondrial catalase is overexpressed. These mice exhibit reduced cardiac ROS and attenuation of nearly all cardiac aging phenotypes.^41,43 Gain- and loss-of-function data of peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), a master regulator of mitochondrial biogenesis, also support an important role for mitochondrial dysfunction in cardiac aging and HF. Genetic deletion of PGC-1α in the heart accelerates the age-related decline in cardiac function and resilience to injury.^44,45 Although forced overexpression of cardiac PGC-1α induces robust mitochondrial biogenesis, it requires careful titration because mitochondrial oversaturation in the heart can also amplify ROS production and induce cardiac failure.^46,47

THERAPEUTIC DEVELOPMENT.

Despite strong evidence supporting a causal role of mitochondrial dysfunction and oxidative stress in cardiac aging and HF, randomized clinical trials of antioxidant interventions in HF have generally been disappointing.⁴⁸ This result in part stems from strategies previously used, which mostly relied on antioxidant supplementation that may not have effectively modulated oxidative stress within the heart. More recently, coenzyme Q (CoQ), a free radical scavenging component of the electron transport chain, and lipoic acid, a cofactor for 2-ketoacid dehydrogenases, have shown promising results in animals and humans.^49,50 CoQ10 declines with age and HF, and lifelong supplementation in rodents effectively reduces age-associated cardiac mitochondrial dysfunction and oxidative stress.⁵¹ Q-SYMBIO (Coenzyme Q10 as adjunctive treatment of chronic heart failure: a randomised, double-blind, multicentre trial with focus on SYMptoms, BIomarker status [Brain-Natriuretic Peptide (BNP)], and long-term Outcome [hospitalisations/mortality]), a randomized trial of CoQ10 treatment in HF, showed that 2 years of CoQ10 improved mortality, HF hospitalization, and NYHA functional class.⁵² Interestingly, trends toward stronger effects were observed in older adults and in those with higher left ventricular ejection fraction. A small pilot study of older adults with HFpEF did not show benefit of CoQ10 on diastolic function or N-terminal pro–B-type natriuretic peptide.⁵³ However, treatment lasted only 4 months, and this trial was not powered to assess HF outcomes. Lipoic acid also improves cardiac mitochondrial function and redox homeostasis, and it can reverse toxic lipid accumulation and dysfunction in animal models of aging and HF.^54,55 A small pilot study of diabetic cardiomyopathy showed that lipoic acid supplementation reduces peripheral biomarkers of oxidative stress and inflammation and improves subclinical cardiac dysfunction.⁵⁶ A trial of patients with diabetes and ischemic cardiomyopathy is now underway to investigate the use of this antioxidant further in HF (Alpha-lipoic Acid in Diabetic Patients With Ischemic Cardiomyopathy; NCT06056687).

Recent work has suggested that directly targeting mitochondrial dysfunction may be more effective. NAD⁺ repletion is one such strategy being investigated (Mechanistic Studies of Nicotinamide Riboside in Human Heart Failure; NCT04528004). NAD⁺ is a critical coenzyme necessary for mitochondrial redox reactions, and its age-associated decline contributes to mitochondrial dysfunction and increased ROS. In animal models of HF, boosting NAD⁺ levels with its precursor nicotinamide riboside improves mitochondrial function, myocardial energetics, and cardiac function.^57,58 Early data in clinical trials show that nicotinamide riboside safely increases NAD⁺ levels and potentially reduces inflammation in humans.⁵⁹ Whether it improves HF outcomes remains to be determined. The mitochondrial targeted peptide, MTP-131 (elamipretide), is another candidate therapeutic being investigated in aging and HF. MTP-131 is a cell-permeable Szeto-Schiller peptide that uniquely concentrates in the inner mitochondrial membrane where it enhances ATP synthesis by inhibiting cardiolipin peroxidation. MTP-131 rapidly restores muscle mitochondrial energetics in older animals and humans,^60,61 and it improves mitochondrial respiration and cardiac function in animal models of HF.^62,63 Although MTP-131 did not improve left ventricular ejection fraction in a small study of patients with HF with reduced ejection fraction (HFrEF),⁶⁴ its effects in HFpEF are still being investigated (Study to Evaluate the Effects of 4 Weeks Treatment With Subcutaneous Elamipretide on Left Ventricular Function in Subjects With Stable Heart Failure With Preserved Ejection Fraction; NCT02814097).

Finally, modulating the associated metabolic reprogramming that occurs in cardiac aging and HF is an alternative strategy to address mitochondrial dysfunction. Perhexiline, an antianginal drug that inhibits mitochondrial carnitine palmitoyltransferase (CPT)-1 and CPT-2, shifts muscle metabolism from FA to glucose use. In patients with HFrEF, perhexiline improved cardiac function, exercise capacity, and muscle energetics.^65,66 Interestingly, despite inducing changes in cardiac and skeletal muscle energetics, perhexiline did not alter substrate use, a finding suggesting that its effects may be mediated by different mechanisms of action. Although no clinical trials are currently underway in older adults with HF, small pilot studies have shown symptomatic benefit in older adults with severe aortic stenosis.⁶⁷ Reducing FA substrate availability to the heart may also attenuate cardiac lipotoxicity generated by a bottleneck effect from impaired mitochondrial FA oxidation in the aged and failing heart.⁶⁸ Circulating levels of FAs (eg, triglycerides) increase with aging, and they can be effectively reduced with omega-3 and omega-6 polyunsaturated FAs (PUFAs). Higher circulating PUFAs have been associated with reduced HF risk in humans,⁶⁹ and in mice, PUFA supplementation can prevent adverse myocardial remodeling and dysfunction induced by pressure overload.⁷⁰ The GISSI-HF (Gruppo Italiano per lo Studio della Sopravivenza nell’Insufficienza Cardiaca–Heart Failure) trial, a double-blind, placebo-controlled randomized clinical trial of nearly 7,000 patients with HF, showed that PUFA therapy reduces mortality and cardiovascular hospitalizations.⁷¹ In older adult men at high risk of CVD, PUFA treatment also showed a trend toward reduced overall mortality, but no differences in cardiovascular events, although HF was not included in this outcome.⁷² Although PUFA supplementation is not specifically being tested in older adults with HF, the generally favorable safety profile and potential efficacy of this intervention may warrant future investigations. Indeed, the overwhelming beneficial effects of sodium glucose co-transporter-2 inhibitors and glucagon-like peptide 1 receptor agonists in HFrEF and HFpEF are likely partly the result of optimization of substrate use, thereby supporting this approach in HF therapeutic development.

DEREGULATED NUTRIENT SENSING

BIOLOGY IN AGING AND DISEASE.

Nutrient sensing pathways not only closely intersect with mitochondria biology, but are also some of the most conserved and powerful regulators of life span.^4,9 An organism’s ability to respond to changes in nutritional states, from nutrient excess to scarcity, provides the metabolic adaptability and stress resilience necessary for optimal function and survival. Nutrients, such as glucose, FAs, amino acids, and ketones, are substrates for energy production and are primarily regulated by 4 major pathways: the insulin/insulin-like growth factor (IGF)-1, mechanistic target of rapamycin (mTOR), sirtuin, and AMK-activated protein kinase (AMPK) pathways. Insulin/IGF-1 and mTOR signaling activate under conditions of nutrient excess, generating an anabolic program in the body, whereas sirtuins and AMPK respond to low-energy states by detecting high levels of NAD⁺ or adenosine monophosphate. In general, the catabolic processes associated with the latter enhance life span, whereas chronic activation of IGF-1 and mTOR pathways tend to accelerate aging and functional decline.

ROLE IN CARDIAC AGING AND HF.

The role of nutrient-sensing pathways in the heart is complex, and their effects on cardiac function and remodeling are highly dependent on context, chronicity, and intensity of activation. For example, exercise transiently activates IGF-1/mTOR/Akt signaling, which is necessary for the physiological cardiac hypertrophy that mediates many of the functional and cardioprotective benefits of exercise.^73,74 However, chronic activation of these anabolic pathways can also lead to unrestrained pathologic hypertrophy and cardiac failure.⁷⁵ Similarly, although decreased IGF-1 signaling is associated with longevity, the age-dependent decline in circulating IGF-1 paradoxically correlates with increased HF risk in older adults.⁷⁶ Recent work in cardiac-specific transgenic mice in which cardiac IGF-1 receptor signaling is chronically enhanced or reduced revealed that the effects of this nutrient-sensing pathway may be age dependent, improving cardiac function in young animals but conversely impairing cardiac autophagy, energetics, and function in old animals.⁷⁷

In cardiac aging, mTOR is among the most extensively studied of the nutrient-sensing pathways. Its increased activity is associated with both age- and chronic stress-induced cardiac hypertrophy and dysfunction, impaired proteostasis/autophagy, and mitochondrial dysfunction.⁷⁸ Although chronic activation of cardiac mTOR induces HF in animal models, the converse is not as straightforward. Complete inhibition of cardiac mTOR activity in adulthood similarly leads to HF by interfering with physiological cardiac growth necessary for survival. However, partial or transient mTOR inhibition with pharmacologic agents, such as rapamycin, exhibits striking beneficial effects in aged animals, by reversing many of the pathologic phenotypes associated with cardiac aging, along with enhancing longevity.^79–81

THERAPEUTIC DEVELOPMENT.

Interest in targeting nutrient-sensing pathways in aging largely stems from the robust and consistent effects of caloric restriction (CR) on longevity in nonhuman animal species. The primary mechanism by which CR enhances life span and health span is through modulation of nutrient-sensing pathways, activation of sirtuins and AMPK, and suppression of mTOR and IGF-1 signaling. In animal models of aging and HF, CR consistently attenuates age-associated cardiac dysfunction, adverse myocardial remodeling, oxidative stress, mitochondrial dysfunction, and loss of proteostasis.⁸² In humans, the effects of CR are not as clear, perhaps in part because these effects may be related to the consistency and intensity of CR regimens. Observational studies have suggested that CR is associated with longer life span, favorable cardiometabolic profiles, and reduced systemic inflammation.⁸³ Although randomized trials have shown that CR interventions lasting 2 years have similar effects on cardiometabolic profiles and inflammation, no significant effects were detected on biological aging, as measured by DNA methylation epigenetic clocks.^83–85 Moreover, whereas CR has been shown to have modest effects on age-associated diastolic dysfunction in healthy older adults and improves exercise capacity in obese older adults with HFpEF, it did not alter cardiac structure or function in the latter group.^86,87 Taken together, these data highlight both the complexity and potential of intervening on nutrient-sensing pathways.

Given the technical and logistical challenges of long-term CR, mimetics, such as rapamycin, are being explored as therapeutic agents for multiple age-associated chronic diseases, including HF. Although the immunosuppressive effects of mTOR inhibitors were an initial concern, clinical studies have shown that these agents actually improve immune function and reduce immunosenescence in older adults.⁸⁸ A small pilot study of older adults with CVD enrolled in cardiac rehabilitation similarly showed that low-dose rapamycin was safe, decreased some senescence and inflammatory markers, and improved physical performance metrics, but not overall frailty.⁸⁹ Early phase clinical trials are now underway to test the efficacy of rapamycin in older adults with HFpEF (Effect of Rapamycin to Improve Cardiac Function in Frail Older Adults; NCT04996719).

AMPK activation is also being explored as a potential therapeutic target, specifically through use of the common diabetes drug, metformin. Metformin is a synthetic biguanide that was first generated more than a century ago and was introduced as a treatment for diabetes in the 1950s. Interestingly, independent of its effects on diabetes, metformin reduces all-cause mortality and incidence of cancer and CVD.⁹⁰ The mechanisms by which metformin enhances health span in older animals is multifold, but they largely stem from the drug’s effects on nutrient-sensing pathways, by suppressing both IGF and mTOR signaling while activating AMPK.⁹¹ In animal models of HF, the cardioprotective effects of metformin are thought to be primarily derived from AMPK activation, which has downstream effects on autophagy, oxidative stress, inflammation, mitochondrial function, and sirtuin activation.^92,93 Current clinical trials are assessing the efficacy of metformin not only in preventing age-related chronic diseases, including HF,⁹⁴ but also in treating HFpEF in older adults (Metformin for Older Patients With Heart Failure With Preserved Ejection Fraction; NCT05093959).

EXERCISE: A QUINTESSENTIAL GEROTHERAPEUTIC INTERVENTION

As highlighted throughout this review, the aforementioned hallmarks of aging do not function independently of each other. Rather, they intersect in a complex network at the cellular and organ level, which essentially dictates a variable and heterogeneous rate of aging in any given individual.^95,96 Addressing this complexity is challenging but in many ways is achieved by exercise. Physical activity affects all hallmarks of aging and enhances resiliency in essentially every organ system.⁹⁷ The aging cardiovascular system is no exception. Exercise not only attenuates or reverses many of the cardiac phenotypes associated with aging, but it also improves inflammation, mitochondrial function, proteostasis, metabolism, epigenetic alterations, telomerase activity, and even regenerative potential of the heart.^3,98–101 Notably, the loss of cardiomyocytes is central to the pathogenesis of HF, and addressing this key deficit has been considered one of the holy grails in the field. Although stem cell interventions in HF have been somewhat controversial, recent studies have shown that exercise, in itself, can enhance the declining regenerative potential of the aging cardiomyocyte.^99,102 Thus, understanding the mechanisms by which exercise promotes cardiomyogenesis could help advance the fields of regenerative medicine and cell therapeutics in HF.

Given the pleiotropic effects of exercise on biological aging and its overwhelming beneficial impact in patients with HF, including older adults,^87,103,104 this lifestyle intervention provides a valuable “gerotherapeutic” tool for not only improving outcomes in older adults with HF, but also gaining new mechanistic insights into the biology of cardiovascular aging. Synergistic efforts in preclinical models, human -omics (MoTrPAC [Molecular Transducers of Physical Activity Consortium]), and interventional clinical trials in older adults with HFpEF (Physical Rehabilitation for Older Patients With Acute Heart Failure With Preserved Ejection; NCT05525663) are underway to investigate the role of exercise in human aging, health, and disease.

BEYOND THE HEART: CONSIDERATION OF GERIATRIC CONDITIONS

A hallmark feature of organismal aging is the relentless, time-dependent decline in physiological reserves across all organ systems. Although each system does not “age” at the same rate, the progression of this process is inevitable in all organ systems, which are interconnected through a complex systemic biology.^95,96 Thus, not only will changes in organ function occur throughout the body, but also the acceleration or slowing of this process in 1 organ can influence the aging and function of other organs. Coupled with interactions with lifestyle and environment, aging leads to widening in the variance of physiological parameters associated with age. This core principle of aging underlies the heterogeneity of phenotypes in older adults with HF (Figure 1).¹⁰⁵

FIGURE 1. Interaction of Biological Aging With Environment and Lifestyle to Generate Heart Failure Phenotype.

Interactive concentric model (adapted from Inouye et al¹⁰⁵) displaying how biological aging interacts with environment and lifestyle to cause geriatric conditions and heart failure (HF) in older adults. Identifying synergistic pathways offers a locus for the rational design and development of targeted interventions and gerotherapeutics

Geriatric conditions reflect this interdependence, representing manifestations of biological aging processes that span multiple organ systems. These conditions occur when the accumulated deficits in multiple systems render an older person vulnerable to situational challenges. Several geriatric conditions, including malnutrition and cachexia, sarcopenia, frailty, and cognitive impairment, coexist with HF in part because of shared mechanisms of dysregulated biological aging, including inflammation, impaired proteostasis, mitochondrial dysfunction, and deregulated nutrient sensing. Table 2 provides definitions of each geriatric condition, key aging processes shared with HF, and their estimated prevalence in HF.^93,99–103

TABLE 2.

Definition and Prevalence of Select Geriatric Conditions

Geriatric Condition	Definition	Key Aging Processes Shared With HF	Prevalence in HF a
Malnutrition	A deficit in protein-energy and micronutrients intake		37%-56%
Cachexia93,99	An extreme form of malnutrition and is defined as a systemic multifactorial catabolic circumstance characterized by generalized wasting of body compositions	Inflammaging	10%-15%
Sarcopenia99,100	Progressive loss of muscle strength, mass, and function Consensus definitions differ: • Per Sarcopenia Definitions and Outcomes Consortium (SDOC) supported by NIA/NIH, defined as "low muscle strength assessed by grip strength and slow gait speed" (ie, slowness) • Per European Working Group on Sarcopenia in Older People 2 (EWGSOP2), defined as "low muscle mass, low muscle strength, and low physical performance"	Impaired proteostasis	20%
Frailty101,102	Clinical circumstance of increased vulnerability resulting from age-associated declines in reserve and function across multiple physiologic systems such that the ability to cope with everyday acute stress is compromised May be operationalized on the basis of physical attributes alone, (operationalized by Fried's criteria) or on the basis of an accumulation of deficits across multiple domains, calculated as a frailty index	Mitochondrial dysfunction	50%
Cognitive impairment103	A limitation in the mental process of acquiring knowledge and understanding; can range from mild cognitive impairment to dementia	Deregulated nutrient sensing	43% on the basis of a recent systematic review

^aPrevalence estimates vary based on numerous factors, including phenotype and severity of heart failure, diagnostic tool used, and study setting.

HF = heart failure; NIA = National Institute on Aging; NIH = National Institutes of Health.

GERIATRIC CONDITIONS AND CLINICAL DECISION MAKING.

Geriatric conditions complicate management in HF given their well-known associations with adverse outcomes, including impaired quality of life, hospitalization, and reduced life expectancy even after adjustment for chronologic age (Table 3). This provides strong rationale for the identification and integration of these conditions into clinical decision making and also clinical trials (in lieu of chronologic age).

TABLE 3.

Known Adverse Outcomes Associated With Geriatric Conditions Among Subgroups of Patients With HF

	Malnutrition	Cachexia	Sarcopenia	Frailty	Cognitive Impairment
HFpEF	↑ Mortality ↑ Hospitalization	↑ Mortality ↑ Symptom burden ↓ QoL	↑ Mortality ↑ Hospitalization ↓ QoL ↑ Exercise capacity	↑ Mortality ↑ Hospitalization ↓ QoL ↑ Disability	↑ Mortality ↑ Hospitalization ↓ QoL ↑ Disability
HFrEF	↑ Mortality ↑ Hospitalization	↑ Mortality ↑ Symptom burden ↓ QoL	↑ Mortality ↑ Hospitalization	↑ Mortality ↑ Hospitalization ↓ QoL ↑ Disability	↑ Mortality ↑ Hospitalization ↓ QoL ↑ Disability
LVAD recipients	↑ Mortality ↑ ICU length of stay ↑ Sepsis	↑ Mortality	↑ Mortality ↑ GI bleeding	↑ Mortality ↑ Hospital LOS	↑ QoL
Transplant recipients	↑ Mortality ↑ Need for MCS ↑ Sepsis ↑ Acute kidney injury	↑ Mortality	↑ Infection	↑ Mortality ↑ Hospital LOS	↑ Mortality

GI = gastrointestinal; ICU = intensive care unit; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LOS = length of stay; LVAD = left ventricular assist device; MCS = mechanical circulatory support; QoL = quality of life.

Identifying geriatric conditions among older adults with advanced HF who are undergoing assessment for left ventricular assist device (LVAD) implantation and orthotopic cardiac transplantation is especially important. Given previous data showing that carefully selected older adults can benefit from these advanced therapies,¹⁰⁶ systematic measurement of geriatric conditions that delineates biological age in individuals with advanced HF could improve these assessments.

Frailty and sarcopenia are particularly important to integrate into decision making for advanced therapies. Frailty is highly prevalent in patients considered for LVAD and orthotopic heart transplantation, irrespective of chronologic age, and it is associated with prolonged hospitalization and mortality in these individuals.^107,108 Sarcopenia is also highly prevalent in HF.¹⁰⁹ Preoperative measures of sarcopenia (through characteristics of the skeletal muscle on computed tomography scan) are associated with increased gastrointestinal bleeding and mortality among patients undergoing LVAD implantation,¹¹⁰ and they are an independent predictor of infection in patients undergoing orthotopic cardiac transplantation.¹¹¹ These common clinical scenarios are illustrative of the importance of geriatric conditions in the clinical management of older adults with HF.

MANAGEMENT OF GERIATRIC CONDITIONS.

Managing geriatric conditions should be part of a comprehensive approach to caring for patients with HF.¹¹² However, there is a paucity of data on the impact of interventions for HF on geriatric conditions. Table 4 outlines potential considerations for managing geriatric conditions when present, as well as interventions under study for directly treating these conditions. Given the close links among biological aging, geriatric conditions, and HF, interventions that improve outcomes in HF could also improve geriatric conditions and related measures. Table 5 summarizes the available data on the effect of HF-specific interventions on geriatric conditions and emerging patient-reported measures especially relevant to older adults. Unfortunately, there are limited data on the effect of HF-specific interventions on geriatric conditions and measures, because of both the systematic exclusion of older adults from many of the landmark studies in HF¹¹³and the lack of geriatric-specific metrics as relevant outcomes. By virtue of their higher baseline risk, the absolute benefits of HF-specific therapies are greatest among older adults, but this benefit can be offset by their attendant risks, which are often increased in the setting of geriatric conditions.¹¹² To leverage emerging gerotherapeutic interventions in HF, future HF studies will need to include older adults with geriatric conditions and incorporate geriatric-specific metrics as end points.

TABLE 4.

Strategies and Potential Interventions for Managing Geriatric Conditions

Geriatric Condition	Strategies for Enhanced Care Provision	Interventions Requiring Additional Study
Malnutrition	• Referral to dietitian/nutritionist • Consideration of nutritional supplements • Dietary recommendations (eg, increasing caloric intake and/or liberalizing dietary restrictions) • Assessment of external factors that may be contributing to malnutrition (eg, financial means, taste, dental issues, social support)	• Dietary modifications • Nutritional/caloric supplementation • Combining nutritional interventions with exercise • Home-delivered meals • Micronutrient supplementation
Cachexia	• Consideration of nutritional supplements • Dietary recommendations (eg, increasing caloric intake and/or liberalizing dietary restrictions) • Consideration for palliative care	• Treatment of underlying causes such as heart failure and other comorbid conditions • Appetite stimulants • Dietary modifications • Nutritional/caloric supplementation
Sarcopenia	• Referral to physical and/or occupational therapy; provision of exercise prescription • Exercise and resistance training • Reassessment of prognosis and risk-benefit ratio of management options	• Treatment of underlying causes such as heart failure (eg, effect of GDMT) and other comorbid conditions • Nutritional/caloric supplementation • Resistance exercise training • Testosterone replacement
Frailty	• Reassessment of prognosis and risk-benefit ratio of management options • Emphasis on lifestyle recommendations such as exercise (home programs, cardiac rehabilitation programs, and strength-training) and nutrition	• Exercise
Cognitive impairment	• Engagement of social support (caregivers, family), services • Referral for formal assessment and/or discussion with other clinicians (geriatrics and/or memory center) • Reassessment of health goals/priorities • Reassessment of prognosis and risk-benefit ratio of management options (especially related to medications) • Consideration of novel agents to treat early Alzheimer dementia if present • Consideration for palliative care	• Treatment of underlying causes such as heart failure and other comorbid conditions • Exercise

GDMT = guideline-directed medical therapy.

TABLE 5.

Effect of Heart Failure-Targeted Therapies on Select Geriatric Conditions and Measures

	Effect on Select Geriatric Conditions				Effect on Select Geriatric Measures
	Malnutrition/Cachexia	Sarcopenia	Frailty	Cognitive Impairment	Functional Capacitya	Days Alive out of Hospital or Home Days	ADL
Beta-adrenergic antagonists	Attenuates and causes partial reversal	No effect	Unknown	Unknown	Worse in HFpEF (better with withdrawal) Improved in HFrEF	Increased	Unknown
ACEI/ARB	Attenuates and causes partial reversal	Unknown	Unknown	No effect	Reduces rate of functional decline	Increased	Improved
ARNI	Unknown	Unknown	Unknown	No effect	Improved	Increased	Improved compared with ACEI
Hydralazine/nitrates	Unknown	Unknown	Unknown	Unknown	Improved	Increased	Unknown
MRAs	Unknown	Unknown	Unknown	Unknown	No effect or improved	Increased	Unknown
SGLT2i	Unknown	Unknown	Unknown	Improved	Improved	Increased	Unknown
GLP 1 RA	Unknown	Unknown	Unknown	Unknown	Improved	Unknown	Unknown
TTR stabilizer	Unknown	Unknown	Unknown	Unknown	Slows the decline	Increased	Unknown
Vericiguat	Unknown	Unknown	No effect	Unknown	Unknown	Increased	Unknown
Cardiac rehabilitation	Unknown	Improved	Improved	Improved	Improved	Unknown	Improved
Aerobic training	Unknown	Improved	Unknown	Improved	Improved	No effect	Unknown
Resistance training	Unknown	Improved	Unknown	Unknown	Improved	Unknown	Unknown
Posthospitalization	Unknown	Improved	Improved	Unknown	Improved	Unknown	Unknown
Cardiac resynchronization	Unknown	Unknown	Unknown	Improved	Improved	Increased	Unknown
Cardiac contraction modulation	Unknown	Unknown	Unknown	Unknown	Improved	Unknown	Unknown
Mitral valve clip	Unknown	Unknown	Unknown	Improved	Improved	Increased	Unknown
Baroreflex simulation	Unknown	Unknown	Unknown	Unknown	Improved	Unknown	Unknown

^aFunctional improvements include changes in NYHA functional class, peak oxygen consumption, or 6-minute walk time.

ACEI = angiotensin-converting enzyme inhibitor; ADL = activities of daily living; ARB = angiotensin receptor blocker; ARNI = angiotensin blocker-neprilysin inhibitor; GLP 1 RA = glucagon-like peptide 1 receptoragonist; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; MRA = mineralocorticoid receptor antagonist; SGLT2i = sodium glucose cotransporter 2 inhibitor; TTR = transthyretin.

CONCLUSIONS AND FUTURE INVESTIGATIONS

The integration of geroscience into HF research not only is providing important new insights into the role of biological aging in HF, but also is beginning to change the therapeutic landscape for this chronic disease. For the field ultimately to leverage the potential of emerging gerotherapeutics in HF, additional work needs to be done to select candidate targets strategically on the basis of causal vs associative aging biology and then optimize implementation strategies, including appropriate patient populations in study design.

As highlighted throughout this review, some of the mechanisms underlying the hallmarks of aging are compensatory processes that are necessary for survival, but they become maladaptive when activated on a long-term basis or inhibited in the aging heart. In other words, not all biological aging is bad. This concept closely aligns with the neurohormonal model of HF pathophysiology, which has been a central tenet in HF therapeutic development for decades. In our effort to target biological aging therapeutically in HF, it is critical that we not only understand its role in physiological cardiovascular aging but also have a robust understanding of how direct manipulation (both gain and loss of function) of candidate targets affects cardiovascular aging and HF phenotypes. This will inevitably require rigorous investigations in preclinical models, not only across their natural life span, but also with targeted interventions at clinically relevant later stages of life in which many of these interventions would be implemented in older adults with HF.

Given the fundamental role of biological aging processes in cellular function and survival, along with the complex interactions among them, intervening on biological aging mechanisms likely will have broad effects. For both preclinical and clinical studies, comprehensive systemic phenotyping will be critical to assessing the safety and efficacy of emerging gerotherapeutics. In future HF trials, it will be important to include older adults more broadly and to integrate geriatric conditions into study design. Geriatric conditions such as frailty and cognitive impairment may be particularly relevant data to collect at baseline to understand better the effect of various pharmacologic and device-based interventions within subgroups of older adults with these conditions. Geriatric conditions could also potentially serve as important outcomes in clinical trials, given the importance of function and cognition on independence and overall well-being. Improved understanding about how various interventions interact with geriatric conditions could provide insights on underlying mechanisms that merit additional investigation.

HIGHLIGHTS.

• Although chronologic age is on a fixed path, biological age may be modifiable.

• Intervening on biological aging could improve on how we treat chronic diseases such as HF.

• Impaired proteostasis, mitochondrial dysfunction, and deregulated nutrient sensing are targets in clinical gerotherapeutic studies.

• Geriatric conditions are a window into aging processes, and they merit integration in clinical decision making and clinical trials in older adults with HF.

ABBREVIATIONS AND ACRONYMS

AMPK

AMK-activated protein kinase

ATP

adenosine triphosphate

CPT

carnitine palmitoyltransferase

CVD

cardiovascular disease

FA

fatty acid

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

IGF

insulin-like growth factor

LVAD

left ventricular assist device

mTOR

mechanistic target of rapamycin

PGC-1

peroxisome proliferator-activated receptor gamma coactivator 1

PUFA

polyunsaturated fatty acid

ROS

reactive oxygen species

TTR

transthyretin

UPR

unfolded protein response

UPS

ubiquitin-proteasome system