Chapter 4

Key Signalling Pathways in Ageing

Ageing is a complex and multifactorial process at the cellular and molecular level. Research shows that key signalling pathways, such as the AMPK, mTOR, the sirtuin, and the insulin/IGF-1 pathway, can be modulated for healthy ageing and disease prevention.

Learn the mechanisms of action behind ageing and discover science-backed frameworks and interventions you can adopt to boost longevity.

AMPK Pathway

AMPK is an enzyme that plays a crucial role in metabolism, growth, and reprogramming. The AMPK pathway is activated in response to energy depletion and promotes several healthy-ageing processes, including autophagy and mitochondrial function [1]. It also prevents cellular senescence, where your cells stop dividing and enter a state of irreversible cell growth, leading to ageing and age-related diseases.

The AMPK pathway can be activated through interventions which induce hormetic stress in the body. This includes frequent physical activity, diet interventions, including intermittent fasting, as well as, supplementation with natural ingredients, such as Resveratrol and Berberine [2].

mTOR Pathway

Mammalian target of rapamycin (mTOR), is an enzyme required for cell growth, proliferation, and survival. It responds to various environmental cues, including nutrient availability, growth factors, and stress signals. mTOR activation leads to ageing and age-related diseases [3].

mTOR activation suppresses autophagy, a process by which cells remove damaged or dysfunctional proteins and organelles, causing accumulated cell damage and ageing. It also leads to an increase in protein synthesis, increasing the risk of protein misfolding and aggregation, as well as, cellular senescence.

Modulation of mTOR activity through interventions, such as caloric restriction, exercising, and NMN supplementation have been shown to extend lifespan and improve healthspan in animal models, suggesting that targeting mTOR signalling may be a promising strategy for promoting healthy ageing [4].

Sirtuin Pathway: NAD+

Sirtuins are a family of proteins involved in regulating cellular metabolism, DNA repair, and stress response [5]. Activation of the sirtuin pathway has been shown to improve mitochondrial function, prevent DNA damage, and reverse the signs of ageing. Calorie restriction, intermittent fasting, Resveratrol, as well as NMN supplementation, are booming as potential anti-ageing interventions, as they boost the sirtuin pathway.

Sirtuins are NAD+ enzymes, meaning they require NAD+ as a co-substrate to carry out their enzymatic function. As NAD+ levels decline with age, the activity of sirtuins may also decline, leading to age-related diseases. By boosting NAD+ levels through supplementation with NAD+ precursors like NMN, the sirtuin and the AMPK pathways can be activated to promote beneficial effects on health [6].

The Avea Bundle is an ideal duo for addressing the NAD+ decline. It consists of a 250mg NMN (Nicotinamide Mononucleotide) pill, and the Booster – a soft gel consisting of carefully selected bioactive ingredients such as Resveratrol, CoQ10, Berberine, and more.

Insulin/IGF-1 Pathway 

Insulin-like growth factor (IGF) is a hormone that regulates growth and development during childhood and adolescence. It manages the effects of growth hormone (GH) in your body. Together, IGF-1 and GH promote normal growth of bones and tissues [7].

As we age, our endocrine system function declines, altering IGF levels. Higher IGF levels promote cellular senescence, leading to age-related diseases such as cancer, metabolic disorders, muscle loss and frailty, as well as neurodegenerative diseases. Caloric restriction, high-intensity interval training, as well as natural compounds such as Resveratrol, have been found to modulate the IGF-1 signalling pathway to boost longevity [8].

NF-kB Pathway

NF-kB is a protein that regulates the expression of genes involved in inflammation, immune responses, and cell survival [9]. It is activated by a variety of stimuli, including infection, injury, and stress. Chronic activation of NF-kB has been linked to many age-related diseases, including neurodegeneration, cardiovascular disease, and cancer.

In ageing, NF-kB activity has been shown to increase, which can contribute to chronic low-grade inflammation, or ”inflammaging” [10]. Longevity supplements alongside healthy lifestyle interventions, may reduce inflammation and delay the onset of diseases.

Heat Shock Response Pathway 

The heat shock response pathway is a protective mechanism activated in response to stress, including heat, oxidative stress, and other environmental stressors. The heat shock response is important for maintaining protein homeostasis and preventing the accumulation of misfolded or damaged proteins [11].

With age, the heat shock response becomes less efficient, leading to the accumulation of damaged proteins that can contribute to age-related diseases. New studies show that boosting the heat shock proteins through sauna can help make your cells more resilient and better adapted and prepared for other damage and stress.

Telomere Maintenance Pathway 

Telomeres are the protective caps at the end of chromosomes that shorten with each cell division. Telomere shortening is a hallmark of ageing and has been linked to cellular senescence and the development of age-related diseases [12].

Telomeres can be maintained through the activity of telomerase, an enzyme that adds telomeric repeats to the ends of chromosomes. Frequent exercise, stress management, as well as Resveratrol supplementation with other antioxidants may boost telomerase activity and protect telomeres, supporting healthy ageing.

PGC-1α Pathway 

The PGC-1α pathway promotes new mitochondrial formation, and reduces oxidative stress and inflammation in the body. Regular exercise or the use of PGC-1α activators, such as NMN, Resveratrol, and Berberine, have been explored as potential anti-ageing interventions [13].

Hippo Pathway 

The Hippo pathway is a signalling pathway that regulates cell proliferation and apoptosis. Dysregulation of the Hippo pathway has been linked to ageing and age-related diseases. Modulating the Hippo signalling pathway by consuming a healthy diet, Omega-3 supplementation, as well as Curcumin, are potential anti-ageing interventions to promote tissue regeneration and delay ageing [14].

FOXO Pathway

Activation of the FOXO pathway has been shown to improve cellular homeostasis, increase lifespan, and delay the onset of age-related diseases in animal models. Resveratrol and polyphenol supplementation, intermittent fasting, regular exercising, and a healthy diet boost the FOXO pathway signalling, delaying the onset of diseases [15].

Wnt Pathway

The Wnt signalling pathway is involved in regulating cellular proliferation, differentiation, and tissue homeostasis [16]. Dysregulation of the Wnt pathway has been linked to ageing and age-related diseases. Activation of the Wnt pathway through frequent exercise, adequate Vitamin D absorption, and probiotics may promote tissue regeneration and delay ageing.

NRF2 Pathway

NRF2 is a protein that regulates the expression of genes involved in cellular stress response, including antioxidant and detoxification enzymes [17].

Activation of the NRF2 pathway has been shown to protect against oxidative stress and inflammation, which are major contributors to ageing and age-related diseases. With age, NRF2 pathway functioning declines, leading to a decrease in antioxidant and detoxification capacity. Regular exercise, intermittent fasting, as well as supplementation with certain antioxidants, such as Resveratrol, can help activate the NRF2 pathway and delay the signs of ageing.

Key Takeaway

Ageing is a reversible process with complex mechanisms. The real target of anti-ageing is not to rejuvenate but to accomplish healthy ageing, which means ameliorating the physiological decline and dysfunction in late life.

Conserved signalling pathways at the cellular and molecular levels, can be modulated to function both individually and in synergy to promote healthy ageing.

Research shows that interventions, such as intermittent fasting, as well as supplementation including NMN (NAD+ precursor), Resveratrol and Berberine, are promising targets for longevity as they stimulate healthy-ageing pathways and consequently lower the risk of age-related diseases.

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