Aging is an inevitable part of life, and chronic diseases that come with it, especially heart failure (HF), pose a life-threatening risk to the elderly population. As a systemic syndrome, heart failure not only impairs cardiac function but also affects peripheral organs such as the kidneys and liver, pushing the elderly body into a vicious cycle. A clinical study published in a renowned academic journal has uncovered a crucial metabolic secret behind very elderly heart failure patients: their blood nicotinamide adenine dinucleotide (NAD) levels are markedly lower than those of healthy individuals, opening up a brand-new path for the clinical management and development of novel therapies for heart failure.

  NAD is an indispensable core coenzyme in the human body, often referred to as the “engine of energy metabolism”. It is involved in the oxidation of all energy substrates including glucose and fatty acids, providing critical support for mitochondrial ATP synthesis. The heart, as the organ with the highest energy consumption in the body, is particularly dependent on NAD. In addition, NAD participates in vital physiological processes such as DNA damage repair and reactive oxygen species (ROS) detoxification, and its homeostatic balance is directly linked to the normal function and survival of cells.

  Previous studies have confirmed that the age-associated decline in tissue NAD levels is a key driving factor for aging-related energy metabolism disorders and the onset of chronic degenerative diseases. For the heart, a high-energy-consuming organ, the reduction in myocardial NAD levels directly leads to mitochondrial dysfunction, causing an imbalance between myocardial energy supply and demand, and ultimately exacerbating heart failure. However, direct clinical data on whether blood NAD levels are abnormal in very elderly heart failure patients has long been lacking.

  To address this question, a research team from top French institutions including Université Paris-Saclay and Assistance Publique-Hôpitaux de Paris conducted a rigorous case-control study. The study enrolled 151 healthy voluntary blood donors aged 19 to 68 years as the control group and 19 very elderly patients aged 75 to 101 years hospitalized for decompensated heart failure as the case group. Using a standardized hot buffered ethanol extraction and quantification method, the team accurately measured whole blood NAD concentrations in both groups and analyzed the correlations between NAD levels and factors such as age, gender, and left ventricular ejection fraction (LVEF).

  The study yielded clear and compelling results: the average whole blood NAD concentration in healthy blood donors was 23.4 μmol/L (SD 4.05), while that in very elderly heart failure patients was only 20.7 μmol/L (SD 3.6), with a statistically significant difference between the two groups (p=0.007). This finding directly confirms that very elderly patients with decompensated heart failure exhibit a significant reduction in blood NAD levels.

  Several other noteworthy details emerged from the research: in the healthy population, overall NAD levels showed no significant correlation with age or gender when analyzed as a whole. However, linear regression analysis revealed a gender difference in the trend of NAD levels with age (p=0.0283): male donors showed a tendency for NAD levels to decline with age, a trend not observed in females. In contrast, among the very elderly heart failure patients, no significant differences in NAD levels were found between genders (p=0.7) or between patients with preserved LVEF (>50%) and reduced LVEF (<50%) (p=0.86). This suggests that the reduction in NAD levels in very elderly heart failure patients is likely a combined result of the disease itself, aging, and comorbidities, rather than being driven by a single clinical indicator.

  So, what causes the drop in NAD levels in very elderly heart failure patients? The research team proposed a plausible explanation: on the one hand, decompensated heart failure leads to insufficient perfusion of vital organs such as the liver and kidneys, impairing the synthesis and circulatory utilization of NAD precursors and reducing their bioavailability. On the other hand, very elderly heart failure patients almost always have multiple comorbidities including hypertension, type 2 diabetes, and atrial fibrillation (with 84.2% having hypertension and 73.7% atrial fibrillation in the study), which form a systemic frailty syndrome. This not only affects nutritional status but also further disrupts energy metabolism, ultimately exacerbating NAD metabolic imbalance.

  The significance of this study extends far beyond revealing a clinical phenomenon; it points to a groundbreaking therapeutic direction for the management of very elderly heart failure—restoring NAD reserves and regulating NAD metabolism may be the key strategy to improve the prognosis of these patients.

  In fact, NAD precursor supplementation therapy has long been a research hotspot in the field of metabolic diseases, and nicotinamide riboside (NR) is one of the most intensively studied and promising NAD precursors to date. Previous preclinical animal studies have confirmed that NR supplementation can effectively maintain myocardial NAD levels and protect cardiac function in heart failure models. Clinical studies have also found that NR supplementation in healthy volunteers significantly elevates blood NAD levels, while improving oxidative stress status and enhancing the body’s antioxidant capacity.

  More importantly, the research team identified a unique metabolic shift in the failing heart: the key enzyme NMRK2, which utilizes NR for NAD synthesis, is upregulated in both mouse and human failing hearts. This means the body of very elderly heart failure patients has an inherent compensatory tendency to “compensate for NAD deficiency”, and exogenous NR supplementation perfectly aligns with this metabolic characteristic. It provides the heart with sufficient NAD precursors, thereby repairing mitochondrial function, improving myocardial energy metabolism, and alleviating heart failure symptoms.

  For clinicians, this discovery also provides a new potential biomarker for heart failure assessment—blood NAD levels may become an important indicator for evaluating the severity and predicting the prognosis of very elderly heart failure patients in the future. For the broader elderly population, it also suggests that maintaining the balance of NAD levels in the body may be an important measure to prevent and delay the onset and progression of heart failure.

  Of course, the clinical application of NAD precursor supplementation therapy in very elderly heart failure patients still requires larger-sample, long-term follow-up clinical trials to verify its safety and efficacy. Critical questions such as the optimal supplementation dose, administration route, and suitable population subgroups all need further exploration. Nevertheless, this study has opened a new door for the treatment of very elderly heart failure.

  With the intensification of global population aging, the number of very elderly heart failure patients is constantly increasing. How to improve their quality of life and survival rate is an urgent clinical challenge. The discovery of the link between NAD metabolism and very elderly heart failure has revealed the enormous potential of metabolic intervention therapy in cardiovascular care. As research advances, it is expected that NAD reserve-restoring therapies will become an integral part of the management of very elderly heart failure patients, bringing new hope for the health of this vulnerable population.

  The fight against aging and disease is an enduring battle, and every scientific discovery is a beacon lighting the way forward. From uncovering the association between NAD levels and very elderly heart failure to exploring the clinical application of NAD precursors, we are getting closer to the essence of the disease and better able to safeguard the health of the elderly.