The review, led by researchers at Changchun University of Chinese Medicine, maps classical TCM gerontology theories onto the fourteen established hallmarks of aging, a framework first articulated by López-Otín and colleagues that includes genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis, extracellular matrix changes, and psychosocial isolation. The authors systematically searched five databases covering literature from 1995 to May 2026, including only experimental studies that assessed anti-aging activity using accepted biomarkers such as senescence-associated β-galactosidase, SASP factors, p16 and p21 expression, telomerase activity, and mitophagy-related proteins.

At the heart of the analysis is a conceptual translation exercise. The most influential TCM paradigm, the Kidney Essence Depletion Theory, holds that aging reflects the gradual exhaustion of congenital essence stored in the kidney. Mechanistically, the review links this to a systemic decline in the NAD+ pool and reduced Klotho expression: NAD+ deficiency impairs SIRT1-mediated deacetylation and PARP1-dependent DNA repair, weakens AMPK restraint on mTORC1, and blocks ULK1-driven autophagy, while Klotho loss disrupts Wnt/β-catenin signaling in bone marrow mesenchymal stem cells. A complementary model, the Kidney Deficiency and Blood Stasis Theory, describes a self-perpetuating feedback loop in which deficiency reduces nitric oxide bioavailability, promotes microvascular hypoxia, activates the NLRP3 inflammasome, and drives TGF-β1/Smad-mediated extracellular matrix stiffening.

Two further theories extend the mapping. The Qi-Blood Theory treats qi as bioenergetic flux and blood as oxygen and substrate delivery; their age-related decline destabilizes the AMPK-mTORC1 nutrient-sensing axis, starves hematopoietic and mesenchymal stem cells of oxygenated perfusion, activates the Rb/p16INK4a senescence pathway, and even converges on reduced metabolic flexibility and social withdrawal. The Spleen-Stomach Theory, focused on nutrient transformation, connects splenogastric decline to disrupted intestinal tight junctions, metabolic endotoxemia via the TLR4/MyD88 pathway, leucine and short-chain fatty acid deficiency, impaired 4E-BP1/S6K1 phosphorylation, and loss of beneficial Bifidobacterium and Lactobacillus populations.

From this theoretical foundation, the review organizes representative formulas into four mechanistic categories. Mitochondrial and autophagy modulators include Zuogui Pill and Yougui Pill, which extend healthspan in Caenorhabditis elegans through PINK1/Parkin-mediated mitophagy, with Zuogui Pill additionally inhibiting Drp1-driven mitochondrial fission and activating AMPK/PGC-1α biogenesis in Alzheimer’s disease models. Kaixin San sustains neuronal mitophagy, clears polyglutamine aggregates via heat shock response, suppresses ferroptosis through SIRT1/FSP1, and reshapes the gut microbiota in Alzheimer’s patients. Guiqi Shen Oral Liquid, derived from a Ming-dynasty formula, achieved a markedly effective rate of 55.56 percent in a clinical study of chronic fatigue syndrome, with ginseng acidic polysaccharide WGPA-A reversing degenerative mitochondrial changes in striated muscle.

The second category targets cellular senescence and the inflammatory microenvironment. Buyang Huanwu Decoction, a classic cardiovascular formula, activates SIRT1 to suppress SASP factors including IL-1β, TNF-α, and IL-6, while its exosomal miR-590-5p reprograms macrophages from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype by targeting SLC8A3. Liuwei Dihuang Wan, a kidney-yin nourishing prescription, reduces p53/p21 expression, protects endothelial cells by inhibiting DNMT1-mediated ERα methylation, activates the YAP-autophagy axis in bone marrow mesenchymal stem cells to counteract bone loss, and restores Lactobacillus abundance in the gut.

Perhaps the most striking clinical evidence concerns the third category, epigenetic and stem cell modulators. In a randomized, double-blind, placebo-controlled trial involving 530 healthy adults, Bazi Bushen Capsules increased telomerase activity by 76.7 percent, an effect the authors equate to a five-year reversal of physiological age. In aged mice, the formula reversed DNA methylation age and upregulated stemness markers OCT4, SOX2, NANOG, and COL17A1, while mechanistic work linked its action to SIRT3-dependent deacetylation of DHRS2 and enrichment of Akkermansia muciniphila via the microbiota-spermidine axis. Guilu Erxian Glue, meanwhile, directly targets hematopoietic stem cell aging by inhibiting p16 expression through histone methylation at the p16Ink4a promoter and modulating the SLAM-SAP pathway to limit T-cell IFN-γ damage.

The fourth category addresses gut microecology and systemic metabolism. Sijunzi Decoction restores beneficial bacteria and short-chain fatty acids in aged rats, upregulates Beclin-1 and LC3-II to protect hippocampal neurons, prevents UVB-induced skin aging, and alleviates osteoporosis through inhibition of PI3K-AKT and p38 MAPK signaling. Yishen Huashi Granule acts on the gut-kidney axis, lowering intestinal permeability and uremic toxins in diabetic kidney disease models while upregulating miR-339-5p to block fibrotic TGF-β1/Smad signaling. Underpinning all four categories are distinct chemical classes: saponins such as ginsenoside Rg1 and astragaloside IV activate AMPK/SIRT1 axes and Parkin-mediated mitophagy; flavonoids like kaempferol, quercetin, and icariin induce mitophagy, suppress SASP, and activate KEAP1-NRF2; polysaccharides remodel the microbiota and protect stem cells; and small molecules such as ferulic acid and tanshinone IIA engage Nrf2 and inhibit ferroptosis. The review emphasizes three modes of synergy—pharmacokinetic, pharmacodynamic, and toxicity-modulating—that distinguish whole formulas from single compounds.

Methodologically, the field is being transformed by artificial intelligence and multi-omics. Machine-learning screening of a TCM compound bank identified 614 potential senolytic compounds across 81 herbs, while proteomic aging clocks built on ultra-high-sensitivity mass spectrometry now quantify biological age across twelve tissue types, pinpointing age 30 as the initial divergence of aging trajectories and ages 45 to 55 as a critical turning point marked by surging pro-aging proteins such as GAS6, GPNMB, COMP, HTRA1, and IGFBP7. Bazi Bushen Capsules have already been shown to reverse DNA methylation age in mice using such tools. The authors caution, however, that AI models trained on well-characterized compound libraries may miss structurally novel actives and struggle to capture multi-component synergy, recommending tight integration with molecular docking against targets such as SIRT1, mTOR, and NF-κB, followed by a progressive validation ladder from C. elegans and Drosophila through rodent models to humans.

Significant obstacles remain before these formulas can enter mainstream geroscience practice. Herbal chemistry varies severalfold with cultivation region, harvest season, and processing, threatening reproducibility; clinical studies remain small and rarely use internationally recognized endpoints such as epigenetic clocks or circulating senescence proteins; and many promising formulas are stalled in basic research for lack of standardized quality markers and long-term safety data. Yet the review argues that the TCM paradigm of low-affinity, multi-component fine-tuning avoids the off-target toxicities and compensatory feedback that have plagued potent synthetic agents such as PI3K/mTOR dual inhibitors. The proposed path forward combines proteomic profiling with TCM constitution typing for patient stratification, uses epigenetic age reversal as a core trial endpoint, and builds a chemical quality control to clinical evaluation pipeline. If successful, this bridge between two millennia of empirical practice and modern aging biology could shift the goal of medicine from merely extending lifespan to compressing morbidity and extending healthspan for a rapidly graying world.

Subject of Research: Anti-aging mechanisms and translational potential of traditional Chinese medicine formulas

Article Title: Traditional Chinese Medicine Formulas in Delaying Aging: From Theoretical Foundations to Molecular Mechanisms and Translational Perspectives

Article References: Jin, C., Du, D., Yu, X., Ji, X., Zhang, X., Li, A., Zu, S., Qu, B., Zhao, D., Wu, D., & Liu, M. (2026). Traditional Chinese Medicine Formulas in Delaying Aging: From Theoretical Foundations to Molecular Mechanisms and Translational Perspectives. Journal of Cellular and Molecular Medicine, 30(19), Article e71371. https://doi.org/10.1111/jcmm.71371

Image Credits: AI Generated

DOI: 10.1111/jcmm.71371

Keywords: traditional Chinese medicine, aging, hallmarks of aging, cellular senescence, mitophagy, telomerase, epigenetic clock, gut microbiota, network pharmacology, proteomic aging clock, herbal formulas, geroscience