Cannabinoids and healthy ageing: the potential for extending healthspan and lifespan in preclinical models with an emphasis on Caenorhabditis elegans

Abstract

There is a significant global upsurge in the number and proportion of older persons in the population. With this comes an increasing prevalence of age-related conditions which pose a major challenge to healthcare systems. The development of anti-ageing treatments may help meet this challenge by targeting the ageing process which is a common denominator to many health problems. Cannabis-like compounds (cannabinoids) are reported to improve quality of life and general well-being in human trials, and there is increasing preclinical research highlighting that they have anti-ageing activity. Moreover, preclinical evidence suggests that endogenous cannabinoids regulate ageing processes. Here, we review the anti-ageing effects of the cannabinoids in various model systems, including the most extensively studied nematode model, Caenorhabditis elegans. These studies highlight that the cannabinoids lengthen healthspan and lifespan, with emerging evidence that they may also hinder the development of cellular senescence. The non-psychoactive cannabinoid cannabidiol (CBD) shows particular promise, with mechanistic studies demonstrating it may work through autophagy induction and activation of antioxidative systems. Furthermore, CBD improves healthspan parameters such as diminishing age-related behavioural dysfunction in models of both healthy and accelerated ageing. Translation into mammalian systems provides an important next step. Moreover, looking beyond CBD, future studies could probe the multitude of other cannabis constituents for their anti-ageing activity.

Keywords: C. elegans,; Cannabidiol,; Endocannabinoid system; Health span,; Lifespan,.

Fig. 1

Chemical structures of endocannabinoids (produced naturally by the body) and major phytocannabinoids (produced by plants). THC, Δ⁹-tetrahydrocannabinol; CBD, cannabidiol; CBN, cannabinol; CBG, cannabigerol; CBC, cannabichromene

Fig. 2

Ageing decreased mRNA expression of cannabinoid CB1R but not CB2R in the PFC of humans with ages ranging from birth to 50 years. PFC, the prefrontal cortex; CB1R, cannabinoid CB1 receptors; CB2R, cannabinoid CB2 receptors; n.s., not significant

Fig. 3

The life cycle of C. elegans at 20 °C and age-related changes that are measured in geroscience research. Under normal laboratory conditions, an adult hermaphrodite produces roughly 300 eggs that hatch after 14 h. In favourable conditions, C. elegans goes through four larval stages (L1 to L4) to the adult in 3–5 days. In unfavourable conditions (overcrowding/low food/high temperature), the L1 larva may choose the dauer larva, which can live for several months. The overall lifespan of C. elegans is 2–3 weeks. Age-related changes in the nervous system, muscle and reproductive system

Fig. 4

Neurodegenerative disease models in C. elegans used to study cannabinoid effects on healthspan and lifespan. Created with www.biorender.com

Fig. 5

A summary of the known anti-ageing mechanisms of CBD in C. elegans. Created with www.biorender.com

Fig. 6

An overview of the anti-aging effects of CBD and THC in rodents, zebrafish, C. elegans and Drosophila

Fig. 7

Rats administered THC by oral gavage for 2 years displayed significantly longer lifespan than vehicle controls. Adapted from the US National Toxicology Program [129, 130]