We know that by manipulating genes, altering the reproductive system, lowering caloric intake, modulating hormone levels, and altering the pathways of IGF-1/insulin, among other things, we can extend the life of invertebrates and mammals and provide them a life that is free from disease. Now, is this applicable to humans? Well, science is trying to find out.
Two billion people on the planet will be over 60 by 2050. The problem is that this increase in longevity is accompanied by an increase in fragility with an increase in associated diseases. Therefore, developing treatments and therapies to intervene in the aging process and the diseases associated with it is a necessity, and we would say, an urgent one.
Dr. Alfonso Galán González – Neolife Medical Team
Calorie restriction (CR) is the most studied intervention when it comes to extending a life that is also free of disease for almost all organisms. In rodents, it can increase life expectancy by up to 50% and lower the onset of age-related diseases, such as diabetes and cancer, as well as cardiovascular, neurodegenerative, and immune diseases.
In the several articles in this blog, we have repeatedly referred to the famous and classic article “Hallmarks of aging”, which lists the 9 determinants or mechanisms of aging known by science (López Otin et al. 2013).
It is not surprising, therefore, that the drugs we will be referring to in this new blog post are aimed at some of those mechanisms and metabolic pathways that we know they regulate. To explain how they work, we will introduce some concepts regarding important metabolic pathways that we will expand on in future blog posts.
Scientific advances in the health sector have significantly prolonged our life expectancy in recent decades. It is estimated that two billion people on the planet will be over 60 by 2050. The problem is that this increase in longevity is accompanied by an increase in fragility, due to an increase in diseases associated with aging, such as diabetes and cancer, as well as cardiovascular, neurodegenerative, and immune diseases, among others. (Butler et al. 2008; Olshansky 2006). Therefore, developing treatments and therapies to intervene in the aging process and the diseases associated with it is a necessity, and we would say, an urgent one. Over the past few decades, several genetic interventions, drugs, and lifestyle interventions have been shown to increase longevity and disease-free longevity in various animal organisms. Over 700 genes associated with aging and longevity have been identified (from Magalhaes 2009). We know that by manipulating genes, altering the reproductive system, lowering caloric intake, modulating hormone levels, and altering the pathways of IGF-1/insulin, etc., we can extend the life of invertebrates and mammals and provide them with a life that is free from disease. Now, is this applicable to humans? Well, science is trying to find out.
Calorie restriction (CR) is the most studied intervention when it comes to extending a life that is also free of disease for almost all organisms. In rodents, it can increase life expectancy by up to 50% and lower the onset of age-related diseases, such as diabetes and cancer, as well as cardiovascular, neurodegenerative, and immune diseases. In primates, it lowers body fat and inflammation, in addition to delaying the onset of diseases (Colman 2009). It acts through the sirtuin pathway and AMPk in addition to inhibiting the mTOR and insulin pathway by improving stress resistance and activating autophagy (Fontana 2010). We will write an article to also explain the AMPk and mTOR pathways, which are very important for understanding both the lifestyle and pharmacological interventions to increase longevity. A long-maintained calorie restriction in humans may lead to undesirable effects such as glucose intolerance, decreased fertility, lower muscle mass, and slower healing (Dirks and Leeuweburgh 2004, 2006). Moreover, asking the population to maintain a sustained lower intake is somewhat complicated, so it is of great interest to develop drugs that mimic calorie restriction.
The substances we will list as follows have an effect on the aging mechanisms known as cell senescence (senolytics), nutrient sensitivity (CR mimetics), and some of these metabolic pathways and enzymes we have mentioned as sirtuins (NAD+, Resveratrol) and mTOR (rapamycin).
It is worth noting at this point that for one of these interventions to be accepted, it must meet three requirements:
- It must significantly extend life and disease-free life.
- It must be validated in three models of organisms.
- It must be confirmed by three independent laboratories.
Also called Sirolimus, it is a drug that has been used for years fundamentally for its immunosuppressive properties and whose use has been found very helpful in this field. It is an inhibitor of the mTOR pathway. In fact, the pathway receives its name precisely because of its relationship with Rapamycin (mechanistic Target Of Rapamycin). The first evidence of its effect in slowing aging in mammals comes from the National Institute of Aging, where it was seen that mice lived longer and were resistant to age-related diseases such as hematopoietic disorders, obesity and cancer, as well as neurodegenerative and cardiovascular diseases (Selman 2009). However, precisely because of its immunosuppressive properties and other severe adverse effects, Rapamycin does not seem to be the most appropriate drug for this purpose in humans. However, this discovery has at least brought the mTOR pathway to our attention and other possible ways to inhibit it.
Metformin is a drug that was initially obtained from French lilac, which we have used for decades to treat type 2 diabetes. It inhibits hepatic gluconeogenesis, improves peripheral glucose utilization, lowers its absorption at the intestinal level, and increases fatty acid oxidation. Its anti-aging effect comes from the activation of the AMPk pathway, which is a kind of sensor of energy levels (as mentioned earlier, we will have another article on this pathway and the mTOR pathway soon). Metformin intake sustained over time has been shown to increase longevity in mice (Martin-Montalvo et al. 2013, Anisimov et al. 2008). Moreover, several studies have shown its ability to reduce the incidence of diseases associated with aging (Papanas et al. 2009). We currently consider Metformin as the top pharmacological candidate for calorie restriction mimetics (CRM).
Compounds that activate sirtuins
Sirtuins are a family of NAD-dependent enzymes that are highly preserved in the creation between species and that play a fundamental role in processes such as energy metabolism, stress response, genomic maintenance, cell proliferation, apoptosis, cancer and, you guessed it, aging. The compounds that activate sirtuins can be one of two types: those of natural origin, usually polyphenols such as Resveratrol or Quercetin and those that are synthetic.
Resveratrol is a polyphenol found in the skin of grapes and blueberries. Its potential for increasing life expectancy and curbing the decline associated with age and the onset of age-associated diseases, such as type 2 diabetes, neurodegenerative and cardiovascular diseases, etc., has been shown in numerous organisms, from yeast to flies, mice (Lagouge et al 2006) and humans, with studies showing that it improves cognitive skills in elderly patients (Witte et al 2014) and even immune function. Hausenblas et al. conducted research to show that the benefits obtained in other species were also applicable to humans (Hausenblas et al. 2015). However, some human studies yield conflicting data (no benefits in metabolic syndrome, counterproductive effects on some cancers (Berman et al. 2017) and fatty liver or poor immune function, etc.) which should be clarified before being safely recommended
As for synthetic compounds used to activate sirtuins, they have various names, such as SRT2104, SRT1720, or SRT2104. Structurally, they have no relation to Resveratrol, and some have up to 1000 times the power to activate SIRT1 than the former. In mice, they have been shown to improve insulin sensitivity, prolong life, lower inflammation, improve mitochondria biogenesis, reduce tumor growth, etc. Studies conducted on human subjects are scarcer, but SRT2104 has been shown to improve lipid and glycemic profile in older smokers (Libri et al. 2012) and improvement of the symptoms of psoriasis lesions. Still, there is a long way to go before they can be widely used in humans.
NAD+ is a cofactor for numerous enzymes, critical for cellular energy metabolism, DNA repair, oxidative and bioenergy stress responses, etc… Its depletion with age has been associated with several aging mechanisms. The molecules to replenish NAD levels may be precursors in the form of nicotinamide (vitamin B3), nicotinic acid, tryptophan, nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), or inhibitors of enzymes that degrade it, like quercetin or apigenin.
Supplementation with NAD+ precursors prolongs life and the disease-free life of different organisms, such as yeasts, flies, worms and mice. In 2016, Trammell et al. demonstrated the bioavailability of NR in humans and its ability to increase NAD+ levels.
Autophagy is a process preserved throughout evolution, which protects cells by removing damaged proteins. With aging, protein control is impaired and damage builds up. Thus, autophagy dysfunction has been linked to degenerative pathologies such as Alzheimer’s and Parkinson’s (Li et al. 2017). Many of the strategies that interfere with the aging process act through the autophagic activity of organisms, such as calorie restriction. Several autophagy-inducing drugs such as the aforementioned Rapamycin and Spermine have been studied. Spermine has been shown to increase longevity in multiple organisms. Concentrations of this compound suffer a significant drop in humans as they age, except in centenarians (Pucciarelli et al. 2012).
Cell senescence – already mentioned in previous articles in this blog – mediated by inflammatory and oxidative stress has proven to be a key mediator of aging. A study, as early as 2011, showed that removing these senescent cells delays the onset of many pathologies associated with aging (Baker et al. 2011). The first senolytics were identified in 2015, dasatinib and quercetin, which, in combination, eliminate senescent cells and improve multiple manifestations of aging in mice. Subsequent studies have shown that even in young mice, they delay the deterioration of several organs by extending life by 25%.
The optimism that this pathway inspires in the delay of aging calls for the senolytic drugs of the future to prove they are not only effective but also safe.
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