With the passing of time, our immune system moves towards a slow and inexorable functional decline, generally coupled with a low-grade inflammatory state and, in some pathologies, to an excessive inflammatory response. This state of local or generalized chronic inflammation (which is accompanied by typical cellular ageing phenomena such as telomeric loss, oxidative stress, and DNA defects) damages all the organs, leading in time to the development of age-related diseases, such as osteoporosis, osteoarthritis, atherosclerosis, neurodegenerative disorders, and cancer. In this article, some perspectives are given on how to revert and modify the ageing process using cannabidiol (CBD) for a healthier longevity.
Homeostasis is defined as a self-regulating process by which biological systems tend to maintain stability while adjusting to environmental changes. If homeostasis is successful, life continues; if maintenance of homeostasis is unsuccessful, the biochemistry of this organism is endangered and disease or death may follow. With all the complexities of a multicellular organism, all the cell communications, genetic mutations, and environmental influences, how do our bodies manage to stay in homeostasis? The answer is the ECS. It is present nearly everywhere in the human body and its role is to protect or re-establish the homeostasis in the body. The ECS is one of the important systems in our body, if not the most important. Its role in the homeostatic function of our body is undeniable, and its range of effects is incredible. Additionally, it also plays a major role in apoptotic diseases, mitochondrial function, and brain function. The ECS also has a profound effect on the regulatory processes in our body.
The ECS may not only provide answers for diseases with no known cures, but it could change the way we approach conditions and symptoms in medicine. Targeting this system would allow us to change our focus from invasive pharmacological interventions (i.e. selective serotonin reuptake inhibitors for depression, benzodiazepines for anxiety, chemotherapies for cancer) to uncovering the mystery of why the body is failing to maintain homeostasis. In the past few years, pharmacological research has focused on the development of synthetic compounds that, by modulating the ECS, could become potential drugs.
Cannabinoids have been shown to have well-documented immunomodulatory activity, and neuroprotective and antioxidative effects that make them good candidates as anti-age molecules. Also, compounds that modulate the endocannabinoid binding and metabolism might be effective as anti-ageing therapeutics. In the context of complex regulative mechanisms, ECBs may play an important role by virtue of their neuro- and immuno-modulatory effects, in the central and peripheral nervous system. One of the options for modulation of the ECS is implementing the non-psychoactive cannabidiol or CBD.
Antioxidants are chemicals that lessen or prevent the effects of free radicals. They donate an electron to free radicals, thereby reducing their reactivity. Antioxidants can lower the formation of free radicals, scavenge them, or enhance their degradation. Unlike other cannabinoids, CBD contains two phenolic groups. It is a strong antioxidant and this effect is achieved by various cellular mechanisms, including the inhibition of oxidative stress and prevention of the generation of reactive oxygen species. Oxidative stress, resulting from an overproduction of ROS, is related to numerous negative effects and can lead to the development or exacerbation of different pathological states and is an important contributor to ageing and age-related symptoms. Research has shown that the endocannabinoid system can modulate oxidative stress and that cannabidiol has a potent antioxidative effect. CBD shows promising pharmacotherapeutic properties, as it lacks psychoactive effects, and has a very good safety profile and antioxidative properties.
Another target of cannabinoids that is important in ageing are the peroxisome proliferator-activated receptors (PPARs). These are a family of nuclear receptors acting as transcription factors that regulate the expression of a plethora of genes involved in metabolism, immune reaction, cell differentiation, and a variety of other cellular changes and adaptive responses. PPARs are activated by a large number of both endogenous and exogenous lipid molecules, including phyto- and endo-cannabinoids, as well as endocannabinoid-like compounds. CBD acts as an agonist of PPAR and some of the proven effects of CBD are due to this agonism (attenuation of neuroinflammation and neurodegeneration). PPAR-γ agonists directly activate genes of the glucose-sensing apparatus in the liver and pancreatic β-cells. Knowing how important stable blood glucose and proper insulin response are for the healthy body and how this becomes dysregulated with age, it is evident that the effects that CBD exerts via the PPAR-γ receptors are pivotal in healthy ageing. CBD might even serve as the basis for the design of new insulin resistance and anti-obesity substances that act as PPAR-γ agonists and support healthy ageing and extend lifespan, by protecting the liver and pancreas and ensuring stable blood sugar levels.
It is a well-known fact that stress causes and accelerates ageing. CBD has been shown to balance the hypothalamic–pituitary–adrenal axis of stress response and is also reported to have anti-depressive actions. CBD regulates the production of hormones in hypothalamus, pituitary, and adrenal glands. It was even shown to modulate the perception of stress stimuli. By means of a number of these effects, CBD had an overall balancing effect on the stress response, lowering the cortisol peaks and protecting the tissues from cortisol-induced damage. The antidepressant effects of CBD are also mediated through several pathways involving activation of 5-HT1A receptors but also the effects CBD has on pro-inflammatory cytokines, free radical species, and oxidants. In recent years, a large body of evidence showed these to be important in the aetiology of depression. One explanation for the effects of CBD is that oxidative stress adversely affects glial cell function and leads to neuron damage in the brain and that CBD counteracts these adverse effects.
Preclinical models have provided great insight into the ageing process with consistent data pointing to the role of insulin secretion/sensitivity and growth hormone in the modulation of longevity. Secretion of the growth hormone and insulin-like growth factor 1 declines over time until only low levels can be detected in individuals aged ≥60 years; this is known as the somatopause. While it is well-known that enhanced insulin sensitivity and low insulin levels are associated with improved survival, there is now ample evidence showing that growth factor and insulin-like growth factor 1 also have profound effects on the lifespan in humans. This idea led to recombinant human growth factor being widely promoted and abused as an anti-ageing drug, despite the many side effects it brings. The activation of cannabinoid receptors appears to modulate insulin secretion and insulin receptor signalling as well as growth hormone production. CBD produces its effects on these hormones through its binding to TRPV2. CBG is also an important phytocannabinoid to consider, as it was proven to impact on the expression of the gene for insulin-like growth factor 1. CBG may have additional positive effects on lifespan due to its interactions with α-2 adrenoceptors and serotonin 1A receptor. A growing body of evidence also suggests that mTOR signalling influences longevity and ageing. mTOR is an evolutionary conserved signalling pathway that coordinates basic cellular and organismal responses such as cell growth, proliferation, apoptosis, and inflammation. Inhibition of the mTOR increases lifespan in all studied model organisms. CBD and CBG have been observed to modulate mTOR signalling, pointing to another mechanism of cannabinoids impacting on longevity. The ability of CBD to suppress the activity of genes involved in some cancers and support mitochondrial function (cellular energy metabolism) is also pivotal in longevity.
Cannabinoids also work at the level of DNA on the telomeres, the caps of DNA at the ends of our chromosomes that function like internal clocks, determining the rate at which we age. They shorten over time, as our cells divide, and when they become short enough, the chromosomes can no longer replicate and the cells die. Many anti-ageing therapies, even gene-therapies, are aimed at telomeres, mostly by impacting on the enzyme telomerase that degrades the telomeres. Interestingly, cannabinoids have been found to significantly decrease the activity of this enzyme. There are several important factors influencing the length of telomeres, with one of the better studied ones being SIRT1. This is a protein that is a member of Silent Information Regulator 2 (Sir2) protein family and it has been shown to be necessary for these protective caps to stay intact. Its expression is critical in several diseases, including metabolic syndrome, cardiovascular diseases, cancer, and neurodegeneration. CBD has been shown to upregulate the expression of SIRT1, adding another piece of the puzzle in healthy ageing and longevity.
A survey carried out in May 2020 showed that 51% of seniors have seen improvement in their quality of life after using CBD and 89% of them would recommend it to friends for recurring health problems. It appears that the long-term use of CBD is safe and no toxicological effect occurs, even in high doses. Animal studies also show the potential of CBD to increase the quality of life and extend life span. Studies in an animal model of nematode Caenorhabditis elegans showed that CBD extended mean lifespan up to 18.3% and increased late-stage life activity by up to 206.4%. This indicates the possibility of CBD to increase lifespan and have a positive effect on the quality of life.
Evidence is mounting that CBD impacts on many of the pathways involved in ageing, thereby acting as a potent molecule for anti-ageing, healthy ageing, and longevity. On the one hand, CBD importantly and positively influences the underlying biological processes of ageing, and on the other, it also addresses many of the symptoms of age-related disorders.
By Dr Erhan Yarar
Dr Erhan Yarar is a translational medical doctor with 20 years of experience in paediatric and adult oncology, endocrinology and, lately, in psychiatry. He is a graduate of Hacettepe University/Turkey and has received several certificates from University of Harvard School of Medicine/USA. He has been involved in several medical collaborations in treating patients in diverse parts of the world, such as the USA, Japan, Israel, Germany, Turkey, and Cyprus
