"Molecules of Longevity : The Power of Gero-Protective Molecules in Defying Time"

In the quest for healthier and longer lives, science has been exploring the fascinating realm of geroprotectors—compounds that hold the potential to promote longevity and delay the ageing process. 

These compounds, also known as potential anti-aging substances, have garnered significant attention in recent years for their promising effects on cellular health and disease prevention.In this newsletter, I delve into the world of geroprotectors and discuss the importance of responsible usage and the need for further clinical investigations to fully understand their safety and efficacy.

The science of ageing and longevity is a fascinating field that explores how our bodies change over time. 

Geroprotectors,  like the mythical fountain of youth in scientific form, have sparked quite the heated debate. Imagine a tug of war between two teams: one believes these substances can stretch our lifespans and keep ageing at bay, while the other team raises a sceptical eyebrow, questioning their actual effectiveness, safety, and whether they're just too good to be true. With no clear winner in sight, the lack of standardised testing methods and official approval only adds extra drama to the show, leaving us all hanging on the edge, wondering if geroprotectors will eventually emerge as the heroes of the villains in the story of ageing.

Picture this: a scientific arena where geroprotectors take centre stage, but they're not alone. They've brought with them a storm of controversy that's electrifying the air. On one side, you have the enthusiasts, waving banners of hope, convinced that these elixirs could be the secret to a longer, healthier life. They point to studies suggesting potential benefits and the tantalising prospect of delaying age-related illnesses.

But wait, there's a rival team in the ring! The sceptics, armed with raised eyebrows and a healthy dose of caution, challenge the hype. They demand concrete proof, wary of false promises and unexpected side effects. The lack of standardised testing methods and regulatory grey areas cast a shadow over the potential benefits, adding a layer of complexity to the debate.

What Are Geroprotective Molecules ?

Geroprotective compounds are substances that have the potential to protect against age-related changes and promote longevity. They are different from other longevity molecules and micronutrients because they specifically target the processes of ageing and age-related damage in our cells and tissues. Geroprotective molecules are more focused on extending lifespan and improving overall healthspan (the period of life spent in good health). They work by supporting cellular repair, reducing oxidative stress, and enhancing the body's natural defence mechanisms against age-related damage.

How do they work ?

Geroprotectors work by interacting with cellular pathways involved in ageing, potentially slowing down age-related processes and promoting longevity. They work through various mechanisms at the cellular level to mitigate the effects of ageing. 

One of the primary ways is by combating oxidative stress. As we age, our cells experience an accumulation of reactive oxygen species (ROS), which can damage cell structures, including DNA, proteins, and lipids. There are claims that geroprotectors with antioxidant properties, such as resveratrol found in red grapes and red wine, can neutralise these harmful ROS, potentially reducing cellular damage and promoting longevity.

Another important mechanism of geroprotectors is their anti-inflammatory effects. Chronic inflammation is associated with many age-related diseases, and by reducing inflammation, geroprotectors can potentially slow down the ageing process. Curcumin, derived from turmeric, is a well-known geroprotector with strong anti-inflammatory properties.

Geroprotectors may also influence certain cellular pathways involved in ageing. For instance, they may activate genes associated with longevity and cellular repair processes, or they may inhibit pathways that promote cell senescence (the process of irreversible cell cycle arrest) or apoptosis (programmed cell death).Furthermore, geroprotectors can enhance the function of mitochondria, the powerhouses of our cells, by promoting mitochondrial biogenesis and improving mitochondrial efficiency. This can increase cellular energy production and reduce oxidative stress.

It's important to note that the exact mechanisms of geroprotectors can vary depending on the specific compound and the context of its use. While some geroprotectors have shown promising results in animal studies and preclinical research, more human trials are needed to fully understand their effects and safety in promoting healthy ageing.

Varying Degrees of Confidence Exist in the Scientific Community regarding Geroprotectors ?

While geroprotectors hold promise in potentially extending human lifespan and promoting healthy ageing, it's essential to acknowledge that their use also carries potential risks and uncertainties.

Absence of Reliable Biomarkers for Geroprotectors 

The absence of reliable biomarkers for geroprotectors can hinder the assessment of their effects on ageing. Without appropriate biomarkers, it becomes challenging to measure and demonstrate the impact of geroprotective interventions accurately. This can slow down research progress, make it difficult to compare different interventions, and impede the development of effective strategies for promoting healthy ageing. Therefore, the identification and validation of relevant biomarkers are essential to advance our understanding of geroprotectors and their potential benefits.

Complexity of Ageing 

There are multiple mechanisms of ageing, which makes studying geroprotectors complex. Some of these mechanisms include telomere shortening, genomic instability, epigenetic changes, cellular senescence, mitochondrial dysfunction, and more. Geroprotectors might target one or several of these mechanisms, making it challenging to design experiments and interventions that comprehensively address the intricate ageing process. Additionally, the interconnectedness of these mechanisms means that changes in one area might impact others, further complicating the evaluation of geroprotective interventions and their effects on ageing.

Commercial Bias and Interests 

The commercial interests surrounding geroprotective supplements can lead to potential bias in their development, marketing, and claims. Companies that produce these supplements may prioritise profit over rigorous scientific evidence, leading to exaggerated or unsupported claims about their effectiveness. This bias can mislead consumers and healthcare professionals and may also divert attention from more evidence-based interventions. 

To ensure that geroprotective supplements are safe and effective, it's important for consumers to critically evaluate claims, rely on reputable sources, and consult with healthcare professionals before incorporating such supplements into their routines.

Lack of Comprehensive Data

 One concern is the lack of comprehensive data on the long-term safety and efficacy of geroprotectors in humans. Most research in this field has been conducted in animal models or based on observational studies, which may not fully translate to human outcomes.Despite the fact that several ageing-preventive pathways are known, most classes of possible geroprotectors remain understudied, especially at the preclinical stage. There is insufficient evidence in conformity with the requisite primary criteria for geroprotectors to draw any broad conclusions. In the long term, for example, the quantity of adverse effects may outweigh the possible advantages. This is quite likely, because the more effective the medicine, the more likely it will have undesirable side effects. Most geroprotector examples now only marginally extend longevity or just in one gender.

Why is it important to Differentiate  Geroprotectors 

A variety of trace elements, vitamins, polyphenols, terpenes, polyamines, and other phytochemicals, as well as manufactured pharmaceutical compounds, exhibit genome-protective and geroprotective properties.

The  naturally occurring  and pharmaceutical  geroprotectors can also be further categorised into macronutrients , micronutrients , medications , sleep agents , testosterone agents ,nootropics and non essential amino acids .

Dividing geroprotectors into categories like micronutrients, pharmaceuticals, and others helps organise and understand their diverse mechanisms and applications. Categorization allows for better research, assessment of their effects, and tailored approaches to addressing the complex process of ageing. Different categories might require distinct testing, regulatory approvals, and considerations, making it essential to classify geroprotectors to ensure safety and efficacy in promoting healthy ageing.

Micronutrient geroprotectors are substances that are believed to have the potential to promote longevity and healthy ageing by targeting specific micronutrient deficiencies that can arise with age. These substances include various vitamins, minerals, and other micronutrients that play essential roles in the body's functioning.

For example, some studies suggest that deficiencies in certain vitamins like vitamin D3 or B12 can become more common as people age and may be linked to age-related health issues. Micronutrient geroprotectors aim to address these deficiencies and support overall health by providing the body with the nutrients it needs to function optimally.

Amino acid geroprotectors refer to specific amino acids that are proposed to have potential benefits in promoting longevity and countering age-related decline. Amino acids are the building blocks of proteins and play crucial roles in various physiological processes in the body.

Certain amino acids are believed to have potential geroprotective effects due to their roles in cellular repair, maintenance, and metabolism. For instance, amino acids like methionine and tryptophan have been studied for their impact on ageing and longevity.

Trace element geroprotectors involve certain minerals and trace elements that are proposed to have potential benefits in promoting longevity and addressing age-related health issues. These elements are essential for various physiological processes in the body, even in small amounts.Examples of trace element geroprotectors include selenium, zinc, copper, and magnesium. These elements play crucial roles in antioxidant defence, DNA repair, immune function, and other processes that can influence ageing and age-related diseases.

Pharmaceutical geroprotectors are compounds developed with the intention of extending lifespan and promoting healthy ageing through targeted interventions and are often prescribed  by the doctors. These compounds are often designed to target specific biological pathways associated with ageing and age-related diseases.

Pharmaceutical geroprotectors are a cutting-edge category of compounds designed to target the ageing process and enhance healthy longevity such as Rapamycin and Metformin. 

Senolytics, represented by drugs like dasatinib and quercetin, are emerging as contenders by selectively eliminating senescent cells linked to ageing-related issues. NAD+ precursors such as NR and NMN hold promise for their potential to boost cellular function and DNA repair. 

While these compounds offer exciting prospects, rigorous research and clinical trials are necessary before they can be considered established pharmaceutical geroprotectors, reminding us that the journey to extending healthy ageing is a complex and ongoing scientific endeavour.

Geroprotectors : SilverBullet for Longevity ?

Specific geroprotective molecules that have recently shown promising results in research or clinical trials include:

1. Rapamycin: Among Pharmaceutical geroprotectors, rapamycin stands out for its ability to influence the mTOR pathway, showing potential in extending lifespan in animal models. Originally used as an immunosuppressive drug, rapamycin has shown promising effects in extending lifespan in various model organisms. It affects the mTOR pathway, which plays a role in cellular metabolism and ageing.  For example Rapamycin improves cognitive impairment and Alzheimer's disease-Like pathology in Mice by restoring mitochondrial abnormality in the Brain. Subsequent study has shown that inhibiting mTOR with the medication rapamycin regularly extends longevity in a variety of creatures, including mice. mTOR signalling governs essential cellular processes such as autophagy, cell proliferation, and protein translation, and blocking these pathways influences ageing and health in model organisms.

2. Metformin: Metformin, primarily used for diabetes, is being explored for its effects on cellular metabolism and its possible impact on extending healthspan. It has attracted attention for its potential geroprotective effects, including its impact on metabolism and inflammation. Metformin has been proven in studies to increase longevity via activating AMPK. Roundworms treated with metformin, for example, have increased AMPK activity and live roughly 20% longer than untreated control animals. Metformin-treated mice were found to live approximately 6% longer than control mice. The TAME clinical study with metformin provided the most tangible example of the progress of a geroprotector towards broad human usage (Barzilai et al. 2016). The TAME study is a set of trials in which 3000 people aged 65 to 79 are monitored for six years. The trials will see if metformin users can lower the risk of age-related chronic illnesses including heart disease, cancer, and dementia when compared to placebo controls.

These compounds show promise in preclinical studies and some early clinical trials, their long-term effects on human health are still being investigated. More research is needed to determine their safety, optimal dosages, and effectiveness in promoting longevity in humans.

While their effectiveness may vary, here are a few other commonly studied geroprotective supplements and how they are thought to work:

1. Resveratrol: Found in red grapes and red wine, resveratrol is believed to activate a group of proteins called sirtuins, which play a role in cellular repair and stress resistance. It may also have antioxidant properties that help reduce cellular damage.
2. Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN): These compounds are precursors to a molecule called NAD+ (nicotinamide adenine dinucleotide). NAD+ is involved in cellular energy production and various cellular processes. By increasing NAD+ levels, NR and NMN may support cellular function and metabolism.These NAD+ precursors have shown promise in preclinical studies for their potential to support cellular function and healthy ageing. The clinical trial included 80 middle-aged healthy adults being randomised for a 60-day clinical trial with once daily oral dosing of placebo, 300 mg, 600 mg, or 900 mg NMN. This trial showed that NMN supplementation is safe and well tolerated at up to 900 mg oral daily doses. 
3. Alpha-ketoglutarate(AKG)- Alpha-Ketoglutarate (AKG) is an organic compound that plays a role in the Krebs cycle, a series of chemical reactions that occur in cells to generate energy. AKG is often used by athletes or people engaged in regular exercise due to its potential to enhance energy production and endurance. A study in mice done at the Buck Institute, one of the world's premier ageing research organisations, discovered that alpha-ketoglutarate increased the lifetime of aged mice by 12%.Alpha-ketoglutarate checks all the criteria for a promising longevity molecule: there is considerable scientific evidence that it increases lifespan in several model species (C elegans, fruit flies, and mice). Alpha-ketoglutarate has anti-aging properties (such as epigenetic and mitochondrial dysfunction).
4. Curcumin (from Turmeric): Curcumin is known for its anti-inflammatory and antioxidant properties. It may help reduce inflammation and oxidative stress, which are associated with ageing and age-related diseases.
5. Omega-3 Fatty Acids: Found in fish oil supplements, omega-3 fatty acids have anti-inflammatory effects and may support heart and brain health, potentially contributing to healthy ageing. Buy Krill oil available at the Mito store to decrease your inflammation.
6. Coenzyme Q10 (CoQ10): CoQ10 is involved in cellular energy production and acts as an antioxidant, protecting cells from oxidative damage. It may help maintain cellular function and support heart health.
7. Vitamin D3: Vitamin D is essential for bone health and immune function. It may play a role in supporting overall health and wellness as we age.
8. Green Tea Extract: Green tea contains polyphenols, including epigallocatechin gallate (EGCG), which have antioxidant properties and may support cellular health.

Only a handful of the known and hypothesised gene pathways regulating longevity have been successfully targeted by individual geroprotective drugs, resulting in improved longevity, indicating the poor efficacy of such techniques. Furthermore, single-target and single-molecule treatments carry major risks and costs due to underestimating the complexity, connectivity, dependency, and continual change in biological systems. It's important to note that while these supplements have shown promise in preclinical studies and some clinical trials, their effectiveness in promoting healthy ageing in humans is still an area of ongoing research. 

So, there you have it – a clash of perspectives that's making the world of geroprotectors a scientific spectacle. It's like watching a thrilling tug of war between possibility and scepticism, leaving us all wondering: will geroprotectors be the knights in shining armour, or just another illusion in the grand tapestry of ageing? Only time will unveil the ultimate victor in this gripping saga.

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