Feature | JACC Family Series: Effect of Biological vs. Chronological Aging on CV Diseases

JACC Family Series: Effect of Biological vs. Chronological Aging on CV Diseases

Aging and its impact on health is not as simple as a number. Biological aging, which may not align with chronological age, has different impacts on the risk for cardiovascular diseases as well as its progression and management. Through eight state-of-the-art reviews, the JACC Journals examine the clinical considerations from biomarkers and genetic factors to lifestyle interventions that influence biological aging, as well as new frontiers of assessment, interventions and treatments, and the ways tools like artificial intelligence (AI) are changing the field. Together, they highlight the potential for tailored prevention and treatment strategies that address both forms of aging.

"There is much for caregivers and cardiovascular researchers to learn about how the linear passing of time from birth to old age, compared with how the accumulation of molecular and cellular changes result in a decline of cognitive and physiological function," writes JACC Editor-in-Chief Valentin Fuster, MD, PhD, MACC, in his introduction to the series.

Along with the series published across the Journals, each paper was presented during a dedicated session at ACC.24, now available on ACC Anywhere. Highlights from the series, along with commentary from the editors-in-chief from the JACC Journals, are below.

Cellular Senescence: A Targetable Risk Factor in CVD

JACC: Basic to Translational Science

Cellular senescence as one of the hallmarks of aging and how the manifestation of a senescence-associated secretory phenotype contributes to age-related cardiac and vascular pathologies, including systemic atherosclerosis, valvular disease, hypertension and stroke, is explored by Manish Kumar, MD, et al., in JACC: Basic to Translational Science.

Studies have demonstrated a connection between a high-fat diet and all three types of senescent cells, as well as the role of senescent cardiomyocytes and interstitial cell population in reperfusion injury. "These senescent cells – although initially intended for tissue repair – can lead to chronic low-grade inflammation if they are not cleared," notes Editor-in-Chief Douglas L. Mann, MD, FACC. "The chronic low-grade inflammation that occurs with cell senescence undercuts almost everything in cardiovascular disease."

The good news, Mann says, is that "it's a druggable pathway." The potential of using this pathway for treatment is illustrated by a preclinical study with the senolytic drug navitoclax that limited reperfusion injury and another study where the drug reduced atherosclerotic lesions and absolute core size in mice, among other studies.

According to Kumar and colleagues, "clinical trials assessing the safety of established senolytics in the context of cardiovascular systems [should] be prioritized." Senolytics, they write, can be improved by further studies identifying the specific types of senescent cells accumulated through cardiovascular diseases and their unique biomarkers.

Biological Aging: A Modifiable Risk Factor For HF

JACC: Heart Failure

In describing current knowledge about mechanisms contributing to the pathogenesis of heart failure (HF), Parag Goyal, MD, MS, FACC, et al., focus on three hallmarks of biological aging: impaired proteostasis, mitochondrial dysfunction and deregulated nutrient sensing. Each is being targeted in therapeutic development for older adults with HF. Their state-of-the-art review shows that while chronologic aging is a fixed path, it may be possible to intervene in biological aging to treat chronic diseases such as HF.

"Premature biological aging is the definition of HF. Maladaptive fibrosis and dysfunction of the heart is, in essence, accelerated aging," says Biykem Bozkurt, MD, PhD, FACC, editor-in-chief of JACC: Heart Failure.

When proteostasis, the process by which cells regulate their protein content, is compromised, misfolded or aggregated proteins accumulate, leading to impairments in cellular function and survival. This impairment disproportionately affects the nervous and cardiovascular systems. Goyal, et al., call the targeted treatment of impaired proteostasis mechanisms in age-related HF a "recent bench-to-bedside success story," with drugs now part of guideline-directed management of cardiac amyloidosis. They also discuss other treatments that will be studied in Phase 3 trials, including one that is a CRISPR-based therapy.

Click here to view the session "Impact of Aging on Cardiovascular Diseases: From Chronological to Biological Insights," on ACC Anywhere.

They also discuss how oxidative stress from mitochondrial dysfunction can accelerate aging phenotypes. The heart has the highest content of mitochondria of all organs, and preclinical studies have provided definitive evidence of a causal role of mitochondrial dysfunction and oxidative stress in cardiac aging. Yet, clinical trials of antioxidant interventions in HF have been "disappointing," according to the authors.

More recent trials with coenzyme Q (CoQ), a free radical scavenging component of the electron transport chain which declines with age and HF, and lipoic acid, a cofactor of 2-ketoacid dehydrogenases, have shown more promise in animals and humans. Recent work also suggests that directly targeting mitochondrial dysfunction by boosting NAD+ (a critical coenzyme necessary for mitochondrial redox reactions) levels may also be effective, as is treatment with perhexiline or omega-3 and omega-6 polyunsaturated fatty acids.

The authors also highlight the importance of exercise, which improves inflammation, mitochondrial function, proteostasis and more, along with attenuating or reversing many of the cardiac phenoytpes associated with aging.

Noninvasive Tracking of Biological Aging of the CV System

JACC: Cardiovascular Imaging

Promoting healthy cardiovascular aging is a global public health priority, write Zahra Raisi-Estabragh, MBCHB, PhD, et al., setting the foundation for their review of how imaging and other noninvasive techniques and cardiovascular biomarkers can be used to understand the aging heart and estimate biological heart age and ultimately guide individual- and population-level interventions to promote healthy aging.

Along with reviewing age-related remodeling in the myocardium, valves, conduction system and vasculature, as well as sex-related cardiovascular remodeling, Estabragh and colleagues discuss technologies that can be used to capture these changes, including in myocardial mass and tissue composition, ventricular volumes, systolic and diastolic function, left ventricular strain, and left atrial volumes and function.

Click here to access the entire JACC Family Series, including an audio introduciton from each editor-in-chief.

"The biological age estimation field is expected to be an area of high activity in coming years because of greater availability of suitable data sets and computing means for analysis and the need to better understand aging processes," write the authors. Big data and AI are integral to this work, and they review studies that illustrate how AI coupled with ECGs, CMR and carotid ultrasound can detect subtle changes and estimate biological age.

Y. S. Chandrashekhar, MD, DM, FACC, editor-in-chief of , agrees. "Is aging inevitable? Does everybody have to age? If you have to age, is there a healthy aging? Or a nonhealthy aging?" These are JACC: Cardiovascular Imaging crucial questions in the field, he says, and imaging markers are starting to help answer these little enigmas.

AI and ECG to Assess Biological Age?

JACC: Clinical Electrophysiology

In JACC: Clinical Electrophysiology, Francisco Lopez-Jimenez, MD, MSC, MBA, FACC, et al., review an innovative approach that uses an AI algorithm to estimate biological age from ECG data and explores its clinical implications. They note that when coupled with AI a standard ECG, which is inexpensive, noninvasive and readily accessible, can allow for "meaningful insight into the difference between biological and chronological age." Additionally, they highlight studies showing a clear association between these meaningful differences and the risk of or worsening of cardiovascular diseases.

"AI-ECG–derived age offers a point-of-care, potentially scalable tool that represents a paradigm shift in screening and risk stratification," say Lopez-Jimenez and colleagues. Kalyanam Shivkumar, MD, PHD, FACC, JACC: Clinical Electrophysiology editor-in-chief, adds: "A hundred years after Einthoven's Nobel Prize, we are pretty much going to say that the next century of the ECG will be even more exciting."

How Does Aging Impact Cardiovascular Diseases?

JACC: Asia

"We need more efforts to find a new way to further expand a healthy life span for humans, through biological aging studies," says Jian'an Wang, MD, PhD, FACC, editor-in-chief of JACC: Asia. "However, it is at least equally important to promote cardiovascular health in aging populations through better control of known risk factors and an improvement of socioeconomic endeavors," especially in regions and countries with a low sociodemographic index.

Aging-related cardiovascular disease is a "synergistic effect" of risk factors and biological aging, Dong Zhao, MD, PhD, et al., write, arguing this effect can be modified. Along with highlighting takeaways regarding risk factors from the Global Burden of Disease Database, Zhao and colleagues chart age-specific cardiovascular disease mortality based on location, sex and social determinants of health, as well as age-specific risks of stroke and cancer mortality. Overall, their review highlights major questions in studies of aging-related cardiovascular disease along with perspectives on real-world patterns of disease.

Comprehensive Geriatric Assessment in TAVR

JACC: Advances

Chronological age should be just the first step in evaluating older patients for TAVR, write Abdulla A. Damluji, MD, PhD, FACC, et al., in JACC: Advances. They suggest the Comprehensive Geriatric Assessment – Frailty Index (CGA-FI) should be integrated into the pre-TAVR evaluation to thoroughly assess physical and cognitive functions and predict postprocedural outcomes.

Their state-of-the-art review encourages the cardiovascular team to familiarize themselves with the CGA-FI, which can be calculated and integrated through a web-based platform. The tool assesses physical health (vision, hearing, multimorbidity, polypharmacy, nutrition, balance/falls); functional status (basic and instrumental activities of daily living, Nagi-Rosow-Breslau functional health scale); neurocognitive status and mood; and socio-environmental status (finances, risk for elder abuse, caregiver stress, living environment).

According to JACC: Advances Editor-in-Chief Candice K. Silversides, MD, FACC, the review contains many "clinical pearls" for practical use and emphasizes the importance of setting clear post-TAVR goals. "It's important to consider what matters most to the patient: their priorities, their values and their preferences," she says.

Interventional Cardiology in Older Adults

JACC: Cardiovascular Interventions

"While we generally focus on hard endpoints in clinical trials," says David J. Moliterno, MD, FACC, JACC: Cardiovascular Interventions editor-in-chief, "in [the older population undergoing intervention] the goals are symptom relief and improved quality of life."

Abdulla A. Damluji, MD, PhD, FACC, highlight that interventional cardiologists are increasingly involved in providing complex care for older individuals, and frequently encounter age-associated risks that affect eligibility for invasive care, decision-making during the intervention, procedural adverse events and long-term management decisions. They emphasize the importance of outlining specific goals of care during the decision-making process and being mindful of additional challenges aging adults will face during the recovery process, as well as their heightened mortality risk.

They also discuss the use of a proposed four-domain framework to evaluate geriatric patients before invasive procedures: frailty and physical status, cognitive function, multimorbidity and quality of life. And they review evidence in older adults related to PCI, CABG, TAVR, transcatheter edge-to-edge repair, peripheral artery disease, cardiogenic shock, carotid artery disease, atrial fibrillation-related stroke and left atrial appendage occlusion.

"Understanding of the aging process and the difference between chronological and biological age, and acquaintance with contemporary risk assessment tools and shared decision-making schemes in the older adult population, are critical for the provision of optimal care in this population," they write.

CVD, Cancer and Aging

JACC: CardioOncology

The dynamic relationship between aging and cardiovascular disease and cancer was the focus of the review by Dina Ioffe, MD, et al., in JACC: CardioOncology, in which they emphasize the need for multidisciplinary care, including a comprehensive geriatric assessment, for older adults with cancer.

Not only are there shared risk factors and biological hallmarks in cardiovascular disease and cancer, the presence of cardiovascular disease or its risk factors can increase the risk of cancer-therapy-related toxicity and must be factored into any care plan.

"All this contributes to this cycle of frailty," says JACC: CardioOncology Editor-in-Chief, Bonnie Ky, MD, MSCE, FACC. "But how do we break this cycle?"

Aging can heighten the risk of cancer, and cancer and cancer therapies can drive biological aging and induce cellular senescence. Cardiovascular disease is the leading cause of noncancer death among patients with cancer, and coronary artery disease, hypertension and HF are the common sequelae of cardiotoxic cancer therapies.

Noting the intersection of geriatric cardiology and geriatric oncology, Ioffe and colleagues write that comorbidities, polypharmacy, and age-related functional and cognitive impairment increase the complexity of the cardiovascular assessment in older adults with cancer. They add that a comprehensive geriatric assessment along with optimizing cardiovascular risk factors before and after cancer treatment is critical to tailoring therapy.

Clinical Topics: Prevention, Hypertension

Keywords: Cardiology Magazine, ACC Publications, Aging, Cardiovascular Diseases, Mitochondrial Diseases, Hypertension, Stroke, Artificial Intelligence