Aging is an inevitable process for all, but scientists are steadily unraveling its underlying mysteries. In 2025, a landmark paper published by the Japanese Society of Anti-Aging Medicine in the journal NPJ Aging—"NAD World 3.0: the importance of the NMN transporter and eNAMPT in mammalian aging and longevity control"—has shed light on the mechanisms of aging, offering new insights.
NAD⁺: The "Key Switch" of Aging NAD⁺ (Nicotinamide Adenine Dinucleotide) is a pivotal molecule in cellular energy metabolism and signal transduction. Since the concept of "NAD World" was first proposed in 2009, scientists have increasingly recognized that the systemic decline of endogenous NAD⁺ levels with age is a key driver of aging—a view supported by a growing body of research over the past decade. In NAD World 3.0, researchers have further deepened the understanding of NAD⁺'s role in regulating aging and longevity. They identified two primary factors contributing to NAD⁺ decline: reduced NAD⁺ biosynthesis and increased NAD⁺ consumption. Chronic low-grade inflammation, also known as "inflammaging," plays a critical role behind these two processes. Inflammaging downregulates the expression of NAMPT (a key enzyme in NAD⁺ biosynthesis) while upregulating the expression of CD38 (an NAD⁺ hydrolase), leading to a significant systemic decrease in NAD⁺ levels. This reduction in NAD⁺ further triggers mitochondrial dysfunction and global epigenetic changes in the nucleus, subsequently contributing to the development of various age-related diseases. NMN and eNAMPT: Critical Regulators of NAD⁺ NAD World 3.0 focuses on NMN (Nicotinamide Mononucleotide) and eNAMPT (extracellular NAMPT). NMN is a key intermediate in NAD⁺ biosynthesis, while eNAMPT is the enzyme that produces NMN. Studies have shown that NMN can be absorbed by cells via a transporter called Slc12a8, thereby rapidly elevating intracellular NAD⁺ levels. This discovery not only reveals NMN's crucial role in maintaining NAD⁺ homeostasis but also provides potential targets for developing new anti-aging interventions. eNAMPT also plays an indispensable role in NAD⁺ regulation. It exists in the bloodstream in the form of extracellular vesicles (EVs) and can be absorbed by cells in specific tissues, thereby promoting NMN and NAD⁺ biosynthesis intracellularly. Interestingly, the secretion of eNAMPT-EVs is regulated by multiple factors, including SIRT1 activity and sympathetic nervous system signals. With age, the secretion efficiency of eNAMPT-EVs decreases, leading to lower circulating eNAMPT levels, which in turn affects NAD⁺ levels and function in multiple tissues throughout the body.
A Multilayered Feedback Regulatory Network NAD World 3.0 proposes a multilayered feedback regulatory network model, in which four key tissues—hypothalamus, skeletal muscle, adipose tissue, and small intestine—are interconnected through NMN/Slc12a8 and eNAMPT-EV-mediated NAD⁺ biosynthesis, collectively regulating aging and longevity in mammals. For example, specific neuron populations in the hypothalamus regulate eNAMPT secretion in adipose tissue, thereby influencing systemic NAD⁺ levels and energy metabolism. Meanwhile, the small intestine absorbs dietary NMN and transports it into the bloodstream via Slc12a8, providing raw materials for systemic NAD⁺ biosynthesis. This complex feedback regulatory network not only reflects the exquisite coordination between various tissues in the organism but also offers a new perspective for understanding the systemic mechanisms of aging. The anti-aging research of NAD World 3.0 provides a comprehensive and in-depth perspective for understanding the complex mechanisms of aging. Aging intervention strategies based on NAD⁺ level regulation are under active investigation. For instance, supplementation with NAD⁺ boosters (such as NADH, NMN, and NR) has been proven to alleviate symptoms in various age-related disease models, including diabetes and cardiovascular diseases. Aging is not irreversible—NAD World 3.0 has lit a beacon. While more research is needed for validation, these findings undoubtedly bring boundless possibilities to the field of anti-aging.
References: Imai SI. NAD World 3.0: the importance of the NMN transporter and eNAMPT in mammalian aging and longevity control. NPJ Aging. 2025 Jan 27;11(1):4.
