Alpha-ketoglutarate (AKG) is a molecule that plays a crucial role in the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle or citric acid cycle. This cycle is a series of chemical reactions that occur within the cells of living organisms, converting nutrients into energy.
The TCA cycle is a central hub for cellular metabolism, and AKG is an important intermediate in this process. It’s generated during the breakdown of carbohydrates, fats, and proteins, and is used to produce energy in the form of adenosine triphosphate (ATP).
AKG also has other important functions in the cell, including:
Nitrogen metabolism: AKG is involved in the metabolism of nitrogen-containing compounds, such as amino acids, which are the building blocks of proteins.
Gene expression: AKG can act as a signaling molecule, influencing gene expression and the production of proteins within the cell.
Stress response: AKG can help regulate the cell’s response to stress, such as oxidative stress caused by the accumulation of reactive oxygen species (ROS).
As we age, the levels of AKG in our blood plasma tend to decrease. This decline may be associated with various age-related changes and diseases, such as:
Reduced energy production: Lower levels of AKG may impair the TCA cycle’s ability to generate energy, leading to cellular dysfunction.
Altered gene expression: Changes in AKG levels may affect gene expression, leading to the production of abnormal proteins or the loss of normal protein function.
Increased oxidative stress: Lower levels of AKG may compromise the cell’s ability to neutralize ROS, leading to increased oxidative stress and damage to cellular components.
Supplementing with AKG has been shown to have various health benefits in animal models, including:
Extended lifespan: AKG supplementation has been found to increase the lifespan of certain organisms, such as worms and fruit flies.
Improved metabolic health: AKG supplementation has been shown to improve glucose tolerance, insulin sensitivity, and lipid metabolism in animal models.
Reduced oxidative stress: AKG supplementation has been found to decrease oxidative stress and increase the activity of antioxidant enzymes in animal models.
While more research is needed to fully understand the effects of AKG supplementation in humans, it appears to have potential as a dietary supplement for maintaining metabolic health and overall well-being.
Rapamycin’s mechanism of action involves inhibiting the mechanistic target of rapamycin (mTOR), a protein kinase that plays a crucial role in regulating cell growth, proliferation, metabolism, and aging. mTOR exists in two distinct complexes, mTORC1 and mTORC2. mTORC1 is more sensitive to rapamycin and is responsible for controlling cell growth and metabolism. mTORC2, on the other hand, is involved in the regulation of cytoskeletal organization, cell survival, and cell metabolism.
Inhibition of mTORC1 by Rapamycin has been shown to have several beneficial effects on age-related diseases and longevity. These include:
Prolonging lifespan: Studies in yeast, worms, flies, and mice have demonstrated that rapamycin treatment can increase lifespan. In mice, rapamycin supplementation has been shown to extend median and maximum lifespan by up to 14% in females and 9% in males.
Delaying aging: Rapamycin has been found to slow down the aging process by reducing age-related damage to cells, improving cellular function, and promoting cellular repair mechanisms.
Improving age-related diseases: Rapamycin has been shown to improve various age-related diseases and conditions, such as diabetes, cardiovascular disease, and neurodegenerative diseases like Alzheimer’s and Parkinson’s.
The exact mechanisms by which rapamycin exerts its anti-aging effects are not fully understood, but several hypotheses have been proposed. Some of these include:
Autophagy enhancement: Rapamycin has been shown to enhance autophagy, a cellular process that helps remove damaged or dysfunctional organelles and proteins, which can contribute to aging.
mTORC1-mediated metabolic regulation: Inhibition of mTORC1 by Rapamycin leads to changes in cellular metabolism, including reduced insulin signaling, increased fat oxidation, and reduced inflammation, all of which may contribute to the anti-aging effects.
Telomere maintenance: Rapamycin has been shown to maintain telomere length, which can help protect against cellular aging.
While Rapamycin shows great promise as an anti-aging therapy, there are still challenges to overcome before it can be widely used in humans. Some of these challenges include:
Side effects: Rapamycin has been shown to have side effects in animals, including immunosuppression, gastrointestinal issues, and impaired glucose tolerance. These side effects need to be carefully evaluated in human clinical trials.
Dose and timing: The optimal dose and timing of Rapamycin administration for anti-aging effects are not yet established and may need to be tailored to individual patients.
Drug delivery: Rapamycin is typically administered orally or intraperitoneally, but alternative drug delivery methods may be needed for more effective and targeted treatment.
Despite these challenges, ongoing research and clinical trials are exploring the potential of Rapamycin as an anti-aging therapy. With further research, Rapamycin may become an important tool in the fight against aging and age-related diseases. However, compared to other nutrients that are essential parts of our Longevity Lifestyle, we remain cautious in the case of Rapamycin because of the above mentioned complexity, specifically regarding potential side effects and dosing.
If you want to learn even more about Rapamycin, you might want to watch this podcast episode by Peter Attia, in conversation with longevity researchers Matt Kaeberlein and David Sabatini.
Astaxanthin, a carotenoid belonging to the xanthophyll subclass, possesses numerous clinical benefits due to its unique cell membrane effects. It neutralizes free radicals and oxidants by accepting or donating electrons without becoming a prooxidant. Its linear structure and polar-nonpolar-polar layout allow it to be precisely inserted into cell membranes, with its polar structure scavenging free radicals in aqueous environments, and its nonpolar segment providing oxidation resistance and electron delocalization.
Clinical trials have demonstrated the efficacy and safety of astaxanthin. In double-blind, randomized controlled trials, it reduced oxidative stress and improved biomarkers of inflammation and immunity. It also decreased triglycerides, increased HDL cholesterol, and improved blood flow in microcirculation models. In a small clinical trial, astaxanthin improved cognition and neural stem cell differentiation and proliferation. It has also been shown to improve vision and eye adaptation in several studies.
Astaxanthin has been shown to have a positive impact on fertility and sperm function. In a clinical trial, men receiving 16 mg of astaxanthin daily for three months had increased sperm linear velocity and decreased sperm oxygen-free radical production, resulting in a significantly higher pregnancy rate compared to the placebo group.
In another trial, astaxanthin was evaluated for its effect on functional dyspepsia. While it did not significantly reduce overall symptoms, the higher dose of 40 mg/day did reduce acid reflux-related symptoms and improve well-being in quality of life questionnaires.
Astaxanthin is mainly obtained through the diet, with seafood being the primary source. It is also used as a feed additive for farmed seafood to enhance its color. Natural astaxanthin is mainly derived from the algae Haematococcus pluvialis, while synthetic astaxanthin is also available. Natural and synthetic astaxanthin differ in chemical composition, bioavailability, purity, and sensory quality.
Clinical studies have shown that natural astaxanthin has a good safety profile, with no serious adverse effects observed even at high doses. In one study, subjects experienced red-colored stools and increased bowel frequency at a dose of 30 mg, but no significant changes were observed in liver parameters at doses of 8 to 12 mg daily.
In Closing
Astaxanthin has been shown to have various benefits for human longevity due to its potent antioxidant and anti-inflammatory properties. It helps protect cells from oxidative stress, reduces inflammation, and improves immune function. Additionally, astaxanthin has been linked to improved cardiovascular health, cognitive function, and sperm quality, which are all important factors for overall longevity.
In the past century, human life expectancy has significantly increased, with over 20% of the world’s 9 billion population expected to live beyond the age of 60 by 2050. Recent research has shown promising results in slowing down aging and extending healthy lifespans (healthspans) n various organisms, from yeast to non-human primates, through interventions that can be classified into lifestyle modifications (lifestyle medicine)and pharmacological or genetic manipulations.
Several genetic pathways have been identified as key regulators of aging and lifespan, making them potential targets for anti-aging therapies. Currently, research is focused on developing compounds that mimic calorie restriction, induce autophagy, and enhance cell regeneration, as well as epigenetically modulating gene activity. These anti-aging agents offer exciting opportunities for the healthcare and pharmaceutical industries. Here, we explain the aging process and introduce some bioactive compounds that could benefit healthy aging and the potential role of lifespan extension.
In this blog post, we will delve into the properties of slow aging and healthy lifespan extension found in natural products derived from diverse biological sources, endogenous substances, pharmaceuticals, and synthetic compounds. We will explore the mechanisms of targets for anti-aging assessment and discuss bioactive compounds that offer benefits in the context of healthy aging, as well as their potential role in extending life span.
What is Aging?
Aging is a universal, evolutionarily conserved process that affects almost all living organisms, characterized by multisystem tissue dysfunction and the development of age-related diseases. However, aging is a modifiable process, with interventions available to extend life, improve health, and treat diseases in various organisms. These findings hold immense significance in biomedicine, as they offer the potential for groundbreaking improvements in health.
Aging can be viewed as the progressive reduction of hemodynamic space, with survival being a continuous struggle between biochemical damage and repair. Various molecular, cellular, and biochemical pathways and networks determine an organism’s survival and lifespan. Age-related changes, such as hormonal declines and immune system remodeling, may not necessarily be detrimental and could be adaptive responses. Stress can also have both beneficial and detrimental effects, depending on factors like frequency, intensity, and duration, as well as energy expenditure and metabolic disorders.
Anti-Aging vs Healthy Aging – or: Lifespan vs Healthspan
This understanding of aging has shifted the focus from “anti-aging” interventions to “healthy aging.” We must move away from disease-oriented research and adopt health-oriented prevention strategies to achieve healthy aging aka longevity. Contrary to the notion that aging is an inevitable part of human nature, numerous interventions have shown promise in slowing aging and increasing healthy lifespan across various organisms, from yeast to non-human primates. Interventions can be categorized into lifestyle changes, such as caloric restriction and exercise, and pharmaceutical/genetic regulation, encompassing a wide range of molecules, including natural products, endogenous substances, approved drugs, and synthetic compounds. There is substantial evidence suggesting that aging interventions can delay and prevent the onset of chronic diseases in adults and older adults, and may safely and effectively extend the healthy lifespan of humans.
Aging Mechanisms
Over the past two decades, several genetic pathways have been identified as key regulators of the aging process and lifespan. As a result, genes within these pathways have emerged as attractive and potential targets for anti-aging therapies. Currently, numerous anti-aging drugs are being developed, targeting various aging mechanisms, including calorie restriction mimics, autophagy inducers, putative cell regeneration enhancers, and epigenetic regulators such as DNA methyltransferase and histone deacetylase inhibitors. While evidence on the overall health benefits of these compounds remains limited, epidemiological studies have begun to explore the long-term consequences of exposure to these compounds on human health. Although not yet ready for human trials, further research is warranted, particularly in the context of age-related diseases and conditions. Initial trials should focus on safety and tolerability, using a small number of subjects and a short duration, to provide early insights into promising compounds and potential candidates for more extensive aging studies.
The Aging Industry
For centuries, the pursuit of rejuvenation and youth maintenance has been a topic of scientific interest. In recent decades, this interest has accelerated the emergence of the anti-aging industry. This area of biomedical research remains a subject of debate. According to estimates, the economic impact of delayed aging and increased healthspan in the United States is projected to be around $7 trillion over the next 50 years. China’s health industry, including anti-aging products, has grown significantly, with a market size exceeding $1.3 trillion annually and an average annual growth rate of over 10%. By 2050, it is projected that the annual size of the health industry will surpass that of the United States, reaching $3.5 trillion, with the anti-aging industry also growing considerably. This presents a massive opportunity for the healthcare and pharmaceutical industries to discover new drug targets based on biogerontology.
Evaluating Aging
Conducting clinical trials to evaluate the anti-aging potential of conventional drugs is a challenging task. Older patients often have multiple diseases and are taking multiple medications, leading to drug-drug interactions and comorbidities that make it difficult to assess the full range of effects of these drugs, whether beneficial or adverse. Additionally, the lack of reliable and detectable biomarkers to measure the effectiveness of anti-aging interventions is another significant challenge. To overcome these obstacles, initial trials should be designed to treat age-related diseases and conditions, with a small cohort, short duration, and primary focus on safety and tolerability. Once promising candidates are identified, longer or more detailed studies can be conducted to focus on anti-aging outcomes.
A drug that extends the lifespan of a model organism, preferably a mammal.
A drug that delays or prevents age-related diseases in mammals.
A drug that inhibits the senescence transition of cells from quiescence to senescence.
These criteria may overlap, and if an intervention aims to extend lifespan, it must also retard diseases associated with aging.
Slow Down, Stop, Reverse Aging
Many plants and fungi, consumed as food, beverages, and spices, contain natural anti-aging compounds that can extend the lifespan of model organisms. These active molecules regulate cellular and physiological pathways affected by calorie restriction (CR) and exercise, mimicking the effects of CR by reducing insulin/IGF-1 signaling and activating autophagy and other stress-resistance mechanisms. These natural products not only increase lifespan but also improve health and quality of life by reducing the development of chronic diseases, including cancer, diabetes, cardiovascular disease, and neurodegeneration.
Anti-Agent Agents
In the table below you find natural products, endogenous substances, drugs, and synthetic compounds that could provide benefits in the aspect of healthy aging and the potential role of healthspn extension. We will discuss their specific benefits in our upcoming posts.
Various strategies exist for using these anti-aging agents, including dietary supplements, increasing the intake of foods rich in these molecules, and consuming probiotics and prebiotics to raise blood levels of these molecules. Several nutrients and natural compounds have been linked to increased lifespan in humans, suggesting that these strategies may be feasible for slowing aging and increasing healthspan. Plant and fungal molecules with anti-aging properties in model organisms may also lead to the discovery and identification of new bioactive compounds for the development of improved CR mimetics to slow human aging.
In addition to those mentioned above, many other compounds have been reported to show anti-aging activity, such as acetic acid, allicin, apigenin, aspalathin, berberine, capsaicin, catalpol, celastrol, garcinol, huperzine, hydroxycitrate, inositol, naringin, piceatannol, and piperlongumine.
These natural products, endogenous substances, drugs, and synthetic compounds are being evaluated and many of them should find their way to consumers as micronutrition. We will discuss their specific benefits in our upcoming posts.
When speaking about companies and institutions that take care of our health, we label them the healthcare industry. In less emotional areas than mankind, such as the Internet of Things (IoT), restoring the functionality of a machine or thing is called repair. Transferred to the field of human medicine, we should rather talk of sick-care, instead of health-care.: as soon as the human organism stops functioning as usual, it is taken care of and repaired. If we take the label healthcare seriously we must change from taking care of the already sick to maintaining a healthy status quo – in other words predictively, we must practice Longevity – Predictive Maintenance for Humans.
What is Predictive Maintenance?
The Industrial concept of Predictive Maintenance has evolved. Its roots can be traced back to the development of condition-based maintenance practices in the late 1950s. Predictive maintenance techniques are designed to help determine the condition of in-service equipment to estimate when maintenance should be performed. This approach promises cost savings over routine or time-based preventive maintenance because tasks are performed only when warranted. Thus, it is regarded as condition-based maintenance carried out as suggested by estimations of the degradation state of an item.
The main promise of predictive maintenance is to allow convenient scheduling of corrective maintenance and to prevent unexpected equipment failures. The key is the right equipment lifetime, increased plant safety, fewer accidents with a negative environmental impact, and optimized spare parts handling.
The connection between Predictive Maintenace and Longevity
Longevity refers to the long duration of individual human life or the ability of something to last for a long time. It can be used to describe the length of one’s lifetime or the durability of an object or concept. In the context of human life, longevity is often associated with the study of methods to extend life and the factors that influence lifespan, such as genetics, lifestyle, and environmental conditions. It is different from life expectancy, which is the statistical average number of years remaining at a given age for a population. The result of a re-analysis of previously incorrectly analyzed data on extreme lifetimes (in the Annual Review of Statistics and Its Application) indicates that any longevity cap would be at least 130 years and possibly exceed 180. And some datasets, the authors report, “put no limit on the human lifespan.”
Why is Longevity the Predictive Maintenace for Humans?
Predictive maintenance and human longevity are similar in that they both involve proactive measures based on data analysis to predict and avoid potential issues. Predictive maintenance uses advanced analytics and machine learning to predict and avoid machine failure, leading to increased productivity, reduced breakdowns, and lower maintenance costs. Similarly, estimating human longevity involves analyzing factors such as lifestyle (epigenetics), genetics, and health data to predict an individual’s remaining healthy life, or healthspan, enabling proactive measures to optimize health and potentially extend lifespan. Both predictive maintenance and human longevity estimation rely on data-driven models to make predictions and take proactive actions to avoid unplanned downtime or health issues.
Most surprisingly, we take predictive maintenance of machines for granted, but we stick with repair services for human beings. Find the error…..
So – why wait?
To promote longevity, one should start engaging in longevity activities as early as possible. Regular exercise is a key factor in promoting longevity and overall health. For optimal health and longevity, it’s recommended to engage in regular exercise, maintain a healthy body weight, eat a balanced diet, and engage in healthful behaviors. Research suggests that as few as 15 minutes of exercise per day may help achieve benefits, which could include an additional 3 years of life, and the risk of premature death may decrease by 4% for each additional 15 minutes of daily physical activity. Team sports like tennis and soccer are also recommended for longevity, as they encourage social interaction as well as exercise. Other factors that can contribute to longevity include maintaining a healthy body weight, eating a balanced diet, adding supplements if needed, and engaging in healthful behaviors.
It’s never too late to start, as a recent study found longevity benefits associated with both life-long and later-in-life exercise. Therefore, it’s important to adopt these habits early on to maximize their benefits for a longer and healthier life.
In this week’s episode of the Lifespan podcast, Professor of Genetics Dr. David Sinclair and co-host Matthew LaPlante cover potential anti-aging interventions that are on the cutting edge. They share the latest research surrounding testosterone replacement therapy (TRT), human growth hormone (HGH), peptide supplementation, exosomes, stem cells, and cellular reprogramming. The idea of human rejuvenation and potential paths towards resetting the aging clock is also discussed.
