Metabolics and Nutrient Sensing

Nutrient Sensing

The mTOR (mechanistic target of rapamycin), AMPK (AMP-activated protein kinase), and sirtuin family of proteins play essential roles in the regulation of metabolic stress and energy balance, enabling biological adaptations in response to environmental signals.

This section of the report describes how genetic variances and environmental factors impact these signalling pathways and balance catabolism ('burn') and anabolism ('grow') to support healthspan and longevity.

Catabolism 'Burn'

When energy levels are low, for example in a fasted state, cells activate pathways to restore energy (ATP) by stimulating glycolysis and lipolysis and autophagy ('self-eating') – whereby old proteins are broken down and recycled.

Adiponectin, coded by ADIPOQ, is a hormone released by adipose tissue that initiates fat burning and glucose uptake. This signal is delivered via adiponectin receptors that activate AMPK. A SNP on ADIPOQ confers lower adiponectin levels, and higher risk of obesity, cardiovascular disease, insulin resistance and type 2 diabetes. Adiponectin can be increased by exercise (especially in overweight individuals), ginger, curcumin, chilli peppers, garlic and manganese.

AMPK is key to maintaining the balance between anabolism and catabolism according to nutrient supply and energy demand. As its name suggests, in response to high AMP (low energy), AMPK stimulates glucose and fatty acid break- down and promotes autophagy. And by blocking mTOR inhibits protein synthesis and fat storage. Given its impacts on appetite, insulin signalling, fat and glucose homeostasis, body weight, and mitochondrial biogenesis, AMPK is a major therapeutic target for the treatment of type 2 diabetes, obesity and other metabolic diseases.

Low energy status may be due to low glucose, fasting, exercise, hypoxia (low oxygen) or damage to mitochondria. Mild mitochondrial toxins including polyphenols – epigallocatechin gallate (EGCG) in green tea, quercetin in red onions, apples, berberine, curcumin, genistein in soy beans, and metformin (the anti-diabetic drug) can have a similar effect. Salicylate (aspirin) is a direct activator of AMPK and acts synergistically with other activators. Alpha-lipoic acid (ALA) has been shown to activate AMPK by increasing cellular calcium (Ca++). Finally, AMPK is activated under conditions of oxidative stress (ROS) independently of cellular ATP status.

The sirtuin (silent information regulator 2 (SIRT)) family of genes influence many biological processes including DNA repair, energy metabolism, autophagy, apoptosis and circadian rhythm. In humans, SIRTs 1, 6 and 7 regulate gene expression in the cell nucleus, SIRT2 is active in the cytoplasm and SIRTs 3, 4 and 5 are located in mitochondria where they regulate metabolism.

SIRTs are induced by, and sensitive to, their cofactor NAD+ and inhibited by NADH. Raised NAD+ (relative to NADH) signals low cellular energy (metabolic stress), similarly to AMP (relative to ATP). As AMPK raises cellular NAD+ levels, the same conditions that induce AMPK also stimulate SIRT1 activity. Conversely, excess nutrition (particularly high glucose), inflammation or insufficient NAD+ supply can inhibit SIRT1.

SIRT1 regulates other genes, inhibiting p53 (tumour protein P53) and NF-KB (nuclear factor kappa-beta), and inducing PGC1A (PPAR-gamma coactivator 1-alpha), FOXO3 (forkhead box protein O3) and SREBF1 (sterol regulatory- element binding transcription factor 1) with various effects on metabolism.

The DNA repair protein PARP1 (poly ADP-ribose polymerase 1) also requires NAD+ as a cofactor, and when DNA is damaged (by environmental toxins, and ageing), increased PARP1 activity can divert NAD+ supply away from SIRT1. Conversely, up-regulation of SIRT1 can balance excess PARP1 activity.

Moderately increased NAD+, AMPK and SIRT1 are considered beneficial to healthspan and lifespan. Increased SIRT1 expression protects against metabolic diseases such as diabetes, obesity and cardiovascular disease.

NAD+ (nicotinamide adenine dinucleotide) can be synthesised from tryptophan or from nicotinic acid, or from precursors – NAM (nicotinamide), a form of vitamin B3 found in yeast, meat, milk and green vegetables, NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide). NAD+ deficiency can occur due to excess consumption by PARP1, for example, insufficient dietary intake, age and genetic variance. Exercise has been shown to reverse age-related declines in NAD+. In laboratory conditions, supplementation with NAD+ precursors (NR and NMN) has been shown to be protective against age-related diseases.

As a transcription factor, PGC1A (PPAR-gamma coactivator 1-alpha) regulates other genes including PPARA (PPAR-alpha), PPARG (PPAR- gamma), SIRT3 and NRF (nuclear respiratory factor). It is involved in mitochondrial biogenesis fatty acid oxidation, glucose utilisation, thermogenesis, angiogenesis and muscle fibre- type conversion toward type I (slow-twitch) fibre. Genetic variances on PGC1A are associated with lower activity and greater risk of developing obesity, and other symptoms of metabolic syndrome.

Caloric restriction, fasting, exercise, ketogenic (high-fat) diet, heat shock therapy (hot tubs, heated pools and saunas), cold exposure, ROS (reactive oxygen species) and other cellular stressors can induce PGC1A, directly and via SIRT1 and AMPK.

PPARA is a major regulator of fat metabolism. It is activated under conditions of energy deprivation and is necessary for ketogenesis, an adaptive response to fasting. It is active in tissues that break down fatty acids – the liver, cardiac, and skeletal muscle. PPARA expression is higher in type I (slow-twitch) muscle, and supports adaptive responses to endurance training, including using fat for fuel. A SNP on PPARA is associated with lower activity, and higher risk of obesity. Resveratrol, isoflavones, flavonoids and PUFAs (polyunsaturated fatty acids) can help to increase PPARA function.

FOXO3 is an important regulator of genes involved in cellular homeostasis, stress response, and longevity. When energy is low, SIRT1 induces FOXO3 which activates other genes involved in gluconeogenesis, and mitochondrial respiration, restoring cellar energy levels. FOXO3 is also activated by oxidative stress (ROS), hypoxia, heat shock, and DNA damage, and induces antioxidant compensatory activities. However, in cancer cells, it can mediate cell survival upon chemotherapy induced genotoxic stress.

A SNP on FOXO3 has been consistently and significantly associated with better healthspan and longevity. The more active version of the gene confers higher insulin sensitivity, better physical and cognitive function in older age, and lower prevalence of cancer and cardiovascular disease. Curcumin, green tea catechins, resveratrol, astaxanthin, beta-hydroxybutyric acid (induced by fasting or exercise), and oestrogen have been shown to increase FOXO3 activity.

Anabolism 'Grow'

When energy levels are high (in a fed state), cells can activate pathways to induce cell maintenance and growth. Whilst growth is vital for younger people, and maintenance is important in mid and older age, excessive nutrient intake can overstimulate mTOR with detrimental effects.

mTOR is a complex of proteins, including mTOR1 (the main target of rapamycin), and mTOR2, which regulate growth and metabolism. mTOR senses amino acids, glucose, growth factors (such as growth hormone and insulin), energy levels and stressors (such as low oxygen). When nutrients (particularly amino acids and glucose) are plentiful, mTOR drives synthesis – of proteins, lipids (via SREBF1) and purines (via a mitochondrial folate cycle). However, when nutrients are excessive, mTOR can become dysregulated leading to insulin resistance and conditions such as diabetes, obesity and depression. Overactive mTOR can promote excessive cell division with increased risk of DNA copying errors leading to cancer. Conversely, mTOR is inhibited by AMPK and therefore by anything that induces AMPK – such as polyphenols and fasting. mTOR is directly inhibited by limiting intake of the amino acids, in particular methionine and leucine.

In summary, mTOR is an important regulator of growth and metabolism. In a scenario of nutrient excess and reduced physical activity, mTOR can become dysregulated and overactive. Limiting intake of animal protein, intermittent fasting, and regular exercise can prevent mTOR excess and support healthspan and lifespan.

The IRS1 (insulin receptor substrate 1) protein transmits signals to insulin and insulin-like growth (IGF-1R) receptors to facilitate glucose uptake by cells. In normal circumstances, mTOR regulates this process by uncoupling (blocking) IRS1 interaction with other receptors, thus creating a negative feedback loop. However, hyperactive mTOR can increase degradation of IRS1, resulting in insulin resistance and type 2 diabetes. In addition, a SNP on IRS1 confers lower activity, with similar consequences.

PARP1 (poly(ADP-ribose) polymerase 1) acts as a first responder that detects DNA damage and then facilitates the choice of repair pathway. It is activated by ROS (reactive oxygen species), elevated glucose, and infection, and promotes transcription of inflammatory genes, including TNF and IL6. Both SIRT1 and PARP1 have a roughly equal affinity for NAD+ but DNA damage can increase PARP1 activity more than 100-fold, depleting NAD+ available to SIRT1. Although PARP1 has important roles to play, over- expression can result in highly inaccurate DNA repair. PARP inhibitor drugs reduce inflammation, improve cardiac and endothelial function, and as a cancer treatment, stop PARP from doing its repair work in cancer cells.

A SNP on PARP1 is associated with up to 50% reduced activity, higher HDL cholesterol, lower 8-OHdG (a measure of DNA damage) and decreased risk of coronary artery disease. Reduced PARP1 activity can increase the availability of NAD+ to support SIRT functions, including energy production and DNA synthesis and repair. Vitamin D is a suppressor of PARP1 activity.

PPARG is a key regulator of glucose homeostasis and adipogenesis. It inhibits the release of free fatty acids and adipocytokines (TNF and leptin) and increases the production of adiponectin, which leads to improved insulin sensitivity in the liver and skeletal muscle. It also promotes fat storage (and differentiation of white and brown fat). A SNP on PPARG confers a reduced expression, lower insulin sensitivity and glucose utilisation, and a higher risk of inflammation, insulin resistance and fatty liver. Carriers may have less efficient peripheral fat storage but an increased risk of fat storage in the liver (may look 'physically healthy' but actually 'metabolically unhealthy'). Curcumin, cinnamon, and omega-3 are natural activators of PPARG.

HIF1A (hypoxia-inducible factor 1-alpha) regulates cellular responses to hypoxic (low oxygen) conditions, and is also upregulated by growth factors, via mTOR. It induces the expression of hundreds of genes including VEGFA and erythropoietin (EPO) which help increase oxygen delivery to hypoxic regions (to compensate for hypoxia). HIF1A also regulates genes that impact energy metabolism – promoting glucose uptake and metabolism (via PPARG), repressing fatty acid oxidation (via PGC1A and PPARA), and supporting cell proliferation and survival.

A SNP on HIF1A is associated with higher activity and reduced risk of developing diabetes (types 1 and 2), and improved wound healing, but dysregulated lipid metabolism associated with atherosclerosis, fatty liver disease (NAFLD), obesity, and cancer. This SNP has been reported as beneficial to athletes participating in power sports, due to increased glucose metabolism and muscle building, with the wild genotype being beneficial to endurance athletes.

VEGFA (vascular endothelial growth factor A) helps to restore and improve oxygen supply by creating new blood vessels in response to injury, exercise and during growth. The variance is associated with significantly higher VEGFA, which is beneficial for endurance and aerobic capability. However, it is also associated with diabetic retinopathy, and tumour growth in the context of cancer. Natural inhibitors of angiogenesis include resveratrol, green tea, ginkgo biloba, quercetin, ginger, cinnamon, curcumin, melon, flavonoids and vitamin E.

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