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.

The criteria for evaluating potential anti-aging drugs include:

1. A drug that extends the lifespan of a model organism, preferably a mammal.
2. A drug that delays or prevents age-related diseases in mammals.
3. 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.

Natural products
Astaxanthin, Curcumin, Morphine, Nordihydroguaiaretic Acid NDGA, Rapamycin, Resveratrol, Sappanone A, Spermidine, Tambulin, Urolithins, Ursolic Acid, Coenzyme Q10, Vitamin A, Vitamin D, Vitamin K2, Quercetin, Caffeic Acid, Rosmarinic Acid, Genistein, EGCG, Protandim, Chicoric Acid, Tyrosol, Fisetin, TA-65, Procyanidins

Endogenous Substances
Alpha-ketoglutarate, Oxaloacetic Acid, Dehydroepiandrosterone DHEA, 17α-Estradiol, S-Linolenoyl Glutathione, Melatonin, Nicotinamide Adenine Dinucleotide NAD+, Nicotinamide Riboside NR, Nicotinamide Mononucleotide NMN

Drugs
Acarbose, Aspirin, (−)Deprenyl, Metformin, Minocycline, Statins, Celecoxib, Doxycycline, Enalapril, Metoprolol, Nebivolol

Synthetic Compounds
Nitrons, Pyridoperimidine Derivatives

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.