Senescence, aging, and age-related diseases represent complex biological phenomena with significant impacts on human health, and metabolism and metabolomics play pivotal roles in understanding their mechanisms and interventions. This comprehensive review integrates multiscale perspectives to elaborate on the intricate relationships among metabolism, cellular senescence, organismal aging, and diseases such as cardiovascular disorders, neurodegenerative diseases, diabetes, and osteoporosis.

Cellular senescence, characterized by growth arrest, senescence-associated secretory phenotype (SASP), morphological changes, and dysfunction in organelles like lysosomes and mitochondria, serves as a key driver of aging. Senescent cells exhibit specific metabolic signatures, including alterations in lipid, amino acid, nucleotide, redox, and transition metal metabolism. For example, lipid metabolism reprogramming involving sphingomyelin-ceramide pathways and polyunsaturated fatty acid (PUFA) accumulation promotes senescence, while mitochondrial dysfunction leads to reduced ATP production and increased reactive oxygen species (ROS). Nucleotide deficiency, particularly in deoxynucleotide triphosphates (dNTPs), triggers cell cycle arrest, whereas redox imbalance, marked by decreased glutathione levels, accelerates senescence. Transition metals like iron and copper accumulate in senescent cells due to impaired autophagy, exacerbating oxidative stress and cellular damage.
Metabolic dysregulation is a hallmark of age-related diseases. In cardiovascular diseases, mitochondrial dysfunction and oxidative stress in endothelial cells contribute to atherosclerosis, while energy metabolism impairment in the heart, such as reduced creatine kinase activity and altered fatty acid oxidation, underlies heart failure. Neurodegenerative diseases like Alzheimer’s and Parkinson’s diseases are associated with abnormal lipid metabolism, including cholesterol accumulation in plaques and sphingolipid dysregulation. Diabetes is linked to mitochondrial dysfunction in pancreatic β-cells and adipose tissue, leading to insulin resistance and impaired glucose metabolism. Osteoporosis involves phospholipid and sphingolipid imbalances, along with mitochondrial and redox metabolism defects that disrupt bone remodeling.

Metabolic interventions offer promising strategies to combat aging and related diseases. Key metabolites such as NAD^+, α-ketoglutarate, and β-hydroxybutyrate have demonstrated effects in extending lifespan and improving metabolic health. NAD+ supplementation restores mitochondrial function and alleviates progeria symptoms, while α-ketoglutarate enhances bone regeneration by modulating epigenetic markers. Targeting metabolic signaling pathways like AMPK and mTOR has shown therapeutic potential; for instance, metformin activates AMPK to improve glucose tolerance, and rapamycin inhibits mTOR to extend lifespan in animal models. Dietary interventions, such as caloric restriction, induce metabolic shifts toward fatty acid oxidation and reduce inflammation, potentially delaying aging.
Advancements in multiscale metabolomics techniques have revolutionized aging research. Single-organelle metabolomics, such as single-lysosome mass spectrometry (SLMS), reveals metabolic heterogeneity in lysosomes during senescence, identifying subpopulations with distinct lipid and amino acid profiles. Single-cell metabolomics methods like single-cell mass spectrometry (SCMS) and capillary electrophoresis mass spectrometry (CE-MS) enable real-time analysis of metabolic changes in individual cells, facilitating the study of cellular senescence and brain aging. Spatial metabolomics techniques, including matrix-assisted laser desorption/ionization mass imaging (MALDI-MSI) and desorption electrospray ionization (DESI), provide insights into metabolite distribution in tissues, such as lipid alterations in Alzheimer’s disease brains. These technologies, despite challenges in metabolite annotation and data analysis, have uncovered novel biomarkers and therapeutic targets.

In summary, this review highlights metabolism as a central regulator of senescence and aging, with metabolic reprogramming serving as both a mechanism and intervention strategy for age-related diseases. Multiscale metabolomics has emerged as a powerful tool to decode metabolic complexities, offering translational opportunities for diagnostics and therapies. While challenges like sample rarity and technical limitations persist, ongoing advancements in technology and interdisciplinary research are expected to drive breakthroughs in understanding aging and developing effective interventions to promote healthy aging.
DOI: 10.1007/s11684-024-1116-0