**Requirements:** 1. Maintain the original format and structure. 2. The translation should be accurate, fluent, and natural. 3. Maintain professionalism and consistency. 4. Only return the translation result; do not add any explanations. **Original Text:** 1. **Introduction** Aging is a natural process in which, as organisms age, the functions of cells and tissues decline, increasing the risk of diseases and death. Alpha-ketoglutarate (AKG), as a potential anti-aging metabolite, can regulate various biological functions, thereby extending lifespan and improving healthspan. AKG is one of the metabolites of the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, and is synthesized within the body. It plays a crucial role in cellular energy metabolism, amino acid/protein synthesis, epigenetic regulation, stem cell behavior and differentiation, fertility and reproductive health, as well as the behavior of cancer cells. AKG exerts its effects through various mechanisms, such as inhibiting mTOR and ATP synthase, regulating DNA and histone demethylation, and reducing the formation of reactive oxygen species (ROS). Here, we summarize the latest findings on studies related to AKG and its impact on lifespan and healthspan, as well as the cellular and molecular mechanisms involved in these processes. AKG is a non-toxic compound that is soluble in water and exhibits high stability in aqueous solutions. The most pronounced functional changes during animal aging include a significant decline in physical performance and fertility, as well as an increased risk of death. 2. **AKG Extends Lifespan and Healthspan in Animal Models** - **C. elegans**: Studies by Chin and colleagues have shown that 8 mM of AKG extended the lifespan of C. elegans by 50%, delayed age-related phenotypes, and reduced oxygen consumption. - **Drosophila**: Su and colleagues found that dietary AKG could increase, enhance, or decrease gene expression changes associated with lifespan extension in Drosophila. 5 μM of AKG extended the lifespan of Drosophila but reduced their reproductive activity. AKG extended lifespan by activating the AMPK signaling pathway, blocking the mTOR pathway, and lowering the ATP/ADP ratio. - **Laboratory Rats**: The calcium salt of AKG (Ca-AKG) extended lifespan by reducing the levels of systemic inflammatory cytokines and inducing the anti-inflammatory cytokine IL-10; it increased the lifespan of female and male rats by 10% and 5%, respectively. Interestingly, it induced higher levels of IL-10 production in female T cells. Studies have also shown that AKG promotes the differentiation of goblet cells, maintains protection of the intestinal epithelium and mucosa, and reduces weight loss, excessive bleeding, and disease activity induced by sodium dextran sulfate. - **Humans**: Human plasma AKG levels decrease significantly between the ages of 40 and 80; dietary supplementation of AKG can compensate for this deficiency. AKG has been used in human clinical trials related to various diseases and shows potential benefits in promoting muscle growth, wound healing, cellular energy status, immunity, and rapid postoperative recovery. It also helps in detoxifying reactive oxygen species (ROS) and serves as part of the oxidative defense mechanism. Studies have indicated that AKG has beneficial effects on skin hydration and barrier function in humans. 3. **AKG Regulates Stem Cells** The reduced differentiation potential and number of stem cells during aging are associated with decreased tissue integrity and health, leading to various age-related diseases. AKG can act as an important cofactor in DNA and histone demethylation, thereby maintaining the naive pluripotent state of mesenchymal stem cells (mESCs). 4. **AKG Supports Fertility and Reproductive Ability** AKG is an effective free radical scavenger and a powerful antioxidant that can react with hydrogen peroxide to form succinate, water, and carbon dioxide. It activates the cellular antioxidant system by enhancing the biosynthesis of glutathione (GSH), thereby improving resistance to oxidative stress. AKG can improve oocyte quality and subsequent embryo development by reducing ROS and preventing apoptosis. It significantly increases the number of mouse blastocysts, the number of inner cell mass (ICM) cells, and embryo growth. Its antioxidant activity may be one of the mechanisms by which it supports oocyte quality and quantity. Long-term use of AKG can delay the decline in female fertility, increase the number and quality of follicles and oocytes, and improve telomere maintenance. 5. **AKG in Cancer Cells** AKG and other TCA cycle metabolites play important roles in cancer. In cancer cells, glycolysis-related reactions are disrupted, and TCA cycle metabolites are diverted from energy production pathways to produce compounds and macromolecules required for cell proliferation, which is a hallmark of cancer cells. Cancer cells can directly convert AKG into succinyl-CoA, allowing the TCA cycle to continue and produce NADH and ATP as energy. AKG can control cell proliferation, migration, and metastasis through various mechanisms in different cancers. 6. **Applications of AKG** Aging is a physiological process that leads to functional decline and reduced ability to regulate metabolic stress. Compared to other longevity-related drugs, AKG has the following advantages: - AKG is a naturally occurring compound in the body. - It has high solubility in water. - It is completely absorbed by the body. - AKG derivatives (such as Ca-AKG) can cross cell membranes. Studies have shown that AKG has beneficial effects in animal models at various concentrations. For example, 8 mM of AKG extended the lifespan of C. elegans by 50%, and 10 mM increased the lifespan of female Drosophila by 23% and that of male Drosophila by 2.8%. Dietary supplementation of AKG can improve AKG levels in the body. Different forms of AKG (such as AKG, Na-AKG, Ca-AKG, Dm-AKG, ornithine ketoglutarate, arginine ketoglutarate) are available for supplementation. However, the stability and permeability of different AKG forms vary; for instance, Dm-AKG has higher stability and cell permeability, suggesting that lower concentrations may have a greater impact on lifespan extension. AKG promotes healthy lifespan and longevity in various organisms, including nematodes, flies, mice, and humans. **References:** Saghi Hakimi, Naeini, Laleh Mavaddatiyan, Zahra Rashid Kalkhoran, Soroush Taherkhani, Mahmood Talkhabi. Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: Evidences and perspectives. Experimental Gerontology (2023)