Bio-Hacking Better Health-Leveraging Metabolic Biochemistry to Maximise Healthspan

Abstract

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.

Keywords: NAD+; ROS; ageing; antioxidant; beta-hydroxybutyrate; hyperinsulinaemia; insulin; ketosis; longevity; mitochondria.

Figure 1

A comparison between the effects of ketosis (blue boxes) versus commonly and chronically not being in ketosis (red boxes) on biomarkers and intracellular markers associated with healthspan and longevity versus chronic diseases associated with ageing. Ageing is a physiological process underpinned by many cellular and molecular mechanisms. Metabolic hormones and metabolites strongly dictate cellular health trajectory and play a crucial role in the development of age-related diseases. Common age-related diseases include cardiovascular diseases (CVD), non-alcoholic fatty liver disease (NAFLD), cancer, type 2 diabetes mellitus (T2DM), hypertension and neurodegenerative disease. Beta-hydroxybutyrate (BHB), glutathione (GSH), insulin-like growth factor 1 (IGF-1), manganese superoxide dismutase (MnSOD), mechanistic target of rapamycin (mTOR), nicotinamide adenine dinucleotide (NAD), phosphatidylinositol 3-kinase (PI3K).

Figure 2

Schematic representation of hyperinsulinemia signalling on intracellular antioxidant regulation dynamics, oxidative damage and mitochondria. Hyperinsulinaemia enforces glucose fuelling, leading to increased hypoxia-signalling pathways and decreased antioxidant expression and activity. This leads to increased reactive oxygen species (ROS) production, leading to increased oxidative stress, damaging oxidative phosphorylation (OXPHOS) proteins and cardiolipin (CL), further increasing inflammatory-signalling pathways, altering mitochondrial morphology leading to dysfunctional mitochondria which signal to upregulate aerobic fermentation, a tumourigenic phenotype. Acetoacetate (AcAc), aryl hydrocarbon receptor nuclear translocators (ARNT), adenosine triphosphate (ATP), beta-hydroxybutyrate (BHB), cardiolipin (CL), hyperinsulinaemia (HI), hypoxia Inducible Factor 1 Subunit α (HIF-1α), hypoxia Inducible factor 1 Subunit β (HIF-1β), hypoxia response element (HRE), insulin receptor (InsR), isocitrate dehydrogenase 2 (Idh2), glutathione oxidised form (GSSG), glutathione reduced form (GSH), nicotinamide adenine dinucleotide (NAD⁺), nicotinamide adenine dinucleotide phosphate (NADP⁺), nuclear factor-kB (NF-kB), oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS), sirtuin 3 (SIRT3), superoxide (O₂^•−), tumour necrosis factor α (TNFα).