Cooper Isabella D, Kyriakidou Yvoni, Petagine Lucy, Edwards Kurtis, Elliott Bradley T
Ageing Biology and Age-Related Diseases, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK.
Antioxidants (Basel). 2023 Sep 11;12(9):1749. doi: 10.3390/antiox12091749.
In the pursuit of longevity and healthspan, we are challenged with first overcoming chronic diseases of ageing: cardiovascular disease, hypertension, cancer, dementias, type 2 diabetes mellitus. These are hyperinsulinaemia diseases presented in different tissue types. Hyperinsulinaemia reduces endogenous antioxidants, via increased consumption and reduced synthesis. Hyperinsulinaemia enforces glucose fuelling, consuming 4 NAD to produce 2 acetyl moieties; beta-oxidation, ketolysis and acetoacetate consume 2, 1 and 0, respectively. This decreases sirtuin, PARPs and oxidative management capacity, leaving reactive oxygen species to diffuse to the cytosol, upregulating aerobic glycolysis, NF-kB and cell division signalling. Also, oxidising cardiolipin, reducing oxidative phosphorylation (OXPHOS) and apoptosis ability; driving a tumourigenic phenotype. Over time, increasing senescent/pathological cell populations occurs, increasing morbidity and mortality. Beta-hydroxybutyrate, an antioxidant, metabolite and signalling molecule, increases synthesis of antioxidants via preserving NAD availability and enhancing OXPHOS capacity. Fasting and ketogenic diets increase ketogenesis concurrently decreasing insulin secretion and demand; hyperinsulinaemia inhibits ketogenesis. Lifestyles that maintain lower insulin levels decrease antioxidant catabolism, additionally increasing their synthesis, improving oxidative stress management and mitochondrial function and, subsequently, producing healthier cells. This supports tissue and organ health, leading to a better healthspan, the first challenge that must be overcome in the pursuit of youthful longevity.
在追求长寿和健康寿命的过程中，我们首先面临着攻克衰老相关慢性疾病的挑战：心血管疾病、高血压、癌症、痴呆症、2型糖尿病。这些都是在不同组织类型中出现的高胰岛素血症疾病。高胰岛素血症通过增加消耗和减少合成来降低内源性抗氧化剂。高胰岛素血症促使葡萄糖供能，消耗4个烟酰胺腺嘌呤二核苷酸（NAD）来产生2个乙酰基；β-氧化、酮体分解和乙酰乙酸分别消耗2个、1个和0个NAD。这会降低沉默调节蛋白、聚（ADP-核糖）聚合酶（PARP）和氧化管理能力，使活性氧扩散到细胞质中，上调有氧糖酵解、核因子-κB（NF-κB）和细胞分裂信号。此外，氧化心磷脂，降低氧化磷酸化（OXPHOS）和细胞凋亡能力；驱动肿瘤发生表型。随着时间的推移，衰老/病理细胞群体增加，发病率和死亡率上升。β-羟基丁酸是一种抗氧化剂、代谢物和信号分子，通过保持NAD的可用性和增强OXPHOS能力来增加抗氧化剂的合成。禁食和生酮饮食会增加酮体生成，同时减少胰岛素分泌和需求；高胰岛素血症会抑制酮体生成。维持较低胰岛素水平的生活方式会减少抗氧化剂的分解代谢，此外还会增加其合成，改善氧化应激管理和线粒体功能，进而产生更健康的细胞。这有助于组织和器官健康，带来更好的健康寿命，这是在追求年轻长寿过程中必须首先克服的挑战。
