Last year a very interesting article was published in eLife (Rapamycin rejuvenates oral health in aging mice) by Jonathan Y An, a dentist-scientist and Acting Assistant Professor at the University of Washington. According to the authors, Rapamycin— a drug that overwhelming evidence suggests is a universal anti-aging drug extending lifespan in all tested models from yeast to mammals — can also rejuvenate the aged oral cavity of elderly mice, including regeneration of periodontal bone, attenuation of gingival and periodontal bone inflammation, and finally induce a revertive shift of the oral microbiome towards a more youthful composition.
Let’s see now why this is important.
Recent epidemiological data in the US population suggest that more than 60% of adults aged 65 years and older have periodontitis (or gum disease or periodontal disease)— an inflammation of the periodontium (the tissue surrounding and supporting the tooth structure), characterized by periodontal bone loss, inflammation of the specialized tissues that surround and support the tooth, and microbiome dysbiosis.
Consequently, the authors decided to treat the age-associated periodontal disease with rapamycin — which directly inhibits the mechanistic target of rapamycin complex I (mTORC1) and extends lifespan and ameliorates a variety of age- related phenotypes — and for that reason aged mice with periodontal bone loss were treated with either vehicle control or rapamycin for 8 weeks.
At the end of this treatment, Jonathan and his colleagues found that the mice treated with rapamycin for 8 weeks had significantly more bone compared to mice that received the control diet. And it gets better, since the increase observed in periodontal bone upon rapamycin treatment reflected inhibition of bone resorption and not attenuation of new bone formation.
Normally, bone homeostasis results from a balance between new bone growth and bone resorption, which is reflected by the ratio of two proteins: RANKL (receptor-activator of nuclear factor-kB ligand) and OPG (osteoprotegerin). In fact, it is known that the deregulation of the balance between these two proteins contributes to bone loss in periodontitis. Moreover, bone loss during aging is associated with greater levels of RANKL, while OPG levels remain relatively stable, resulting in an increase in the RANKL:OPG ratio indicative of bone resorption exceeding bone formation.
To make a long story short, Jonathan and his colleagues managed to suppress these age-associated defects in bone homeostasis during an eight weeks treatment of aged mice with rapamycin, demonstrating that rapamycin reverses periodontal bone loss in the aging murine oral cavity at least in part through inhibition of bone resorption (osteoclasts).
Moreover, aging is known to be associated with chronic accumulation of pro-inflammatory factors (commonly known inflammaging), with the nuclear factor-kB (NF-kB) being a hub of immune and inflammatory response activated both during normal aging and as a consequence of periodontal disease, and IkBa functioning as a negative regulator of NF-kB. Keep also in mind that NF-κB affects also the bone homeostasis, since NF-κB signaling mediates RANK ligand-induced osteoclastogenesis.
In particular, when the IkBa levels were measured in both the gingival tissue and periodontal bone, a decrease of IkBa levels was found, indicating an age-associated increase in NF-kB inflammatory signaling in the periodontium. Consistent with the increase in NF-kB signaling, the researchers also found elevated expression of several cytokines in both the gingival tissue and the periodontal bone. Hopefully, an eight weeks rapamycin treatment was sufficient to reverse all these changes (NF-kB , cytokines and osteoclasts) restoring a youthful inflammatory state in both the gingiva and periodontal bone of mice and reducing bone resorption always via RANKL-NF-kB.
But it gets better, since the rapamycin treatment remodeled the oral microbiome in mice.
As a matter of fact, researchers have known for many years that dysbiotic shifts in the oral microbiome are thought to play a significant role in the progression of periodontal disease in humans.
Consequently, Jonathan and his colleagues evaluated the effects of rapamycin on the aged oral microbiome and results indicated a significant increase in species richness during aging that rapamycin attenuated. In particular, among the most notable alterations in taxonomic abundance between groups was the reduction of Bacteroidetes phylum in the rapamycin- treated aged miced. The Bacteroidetes phylum consists of over 7000 different species and includes bacteria associated with human periodontal disease such as Porphyromonas gingivalis, Treponema denticola and Bacteroides forsythus. Further, both the Firmicutes and Proteobacteria phyla also showed a significant difference that was age dependent, but was not significantly altered by rapamycin treatment.
Taken together, this study demonstrated that a short-term treatment with rapamycin in aged mice is sufficient to reverse three clinically defining features of periodontal disease:
- periodontal bone loss,
- periodontal inflammation, and
- pathogenic changes to the oral microbiome.
This work is very important and according to the authors suggests several interesting questions that it will be very important to evaluate in future studies. One such question is whether the effect of rapamycin on the aged periodontium will persist after the treatment period or will rapidly revert back to the aged state. And another question is whether the rapamycin treatment (a bacteria-derived immunosuppressant initially developed as an antifungal agent) and associated mTORC1 inhibition reverting oral microbiome dysbiosis, is only due to inflammation inhibition or there is more to this story?
Thanks for reading, and don’t forget to monitor your comprehensive aging status, including immune aging, with the AgeCurve test.
*Disclaimer: This information is for educational purposes only.
(Cover Photo By Lesly Juarez)