Rapamycin toothpaste stops and reverses periodontal disease --- study says

[TruffleGnocchi]

Rapamycin rejuvenates oral health in aging mice​

Periodontal disease is an age-associated disorder clinically defined by periodontal bone loss, inflammation of the specialized tissues that surround and support the tooth, and microbiome dysbiosis. Here, we demonstrate that short-term treatment with rapamycin rejuvenates the aged oral cavity of elderly mice, including regeneration of periodontal bone, attenuation of gingival and periodontal bone inflammation, and revertive shift of the oral microbiome toward a more youthful composition.

Our data demonstrate 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.

 

[SaltiestSardine]

Where did you get toothpaste from? It was used orally in feed and i don't think a rapamycin toothpaste would do much of anything to repeat the outcome. A quick gloss over the study seems to suggest the results were achieved because of how rapamycin remodels gut bacteria and inhibits certain markers of inflammatory aging through the creation of certain commensal species and inhibition of others.

If anything, this is an argument against the sterile gut nonsense that is perpetuated here, but it is a rat study and it only lasted 8 weeks, so it's not really indicative of any outcome

 

[Ben.]

Where did you get toothpaste from? It was used orally in feed and i don't think a rapamycin toothpaste would do much of anything to repeat the outcome. A quick gloss over the study seems to suggest the results were achieved because of how rapamycin remodels gut bacteria and inhibits certain markers of inflammatory aging through the creation of certain commensal species and inhibition of others.

If anything, this is an argument against the sterile gut nonsense that is perpetuated here, but it is a rat study and it only lasted 8 weeks, so it's not really indicative of any outcome

How? i dont understand that conclusion. one could spin it the other way around and say it is a argument for a "sterile" gut (assuming it was possible) just aswell. More likely however could it be that fungal infections are far more at the heart of diseases then is believed/acknowledged.

 

[TruffleGnocchi]

Where did you get toothpaste from? It was used orally in feed and i don't think a rapamycin toothpaste would do much of anything to repeat the outcome. A quick gloss over the study seems to suggest the results were achieved because of how rapamycin remodels gut bacteria and inhibits certain markers of inflammatory aging through the creation of certain commensal species and inhibition of others.

If anything, this is an argument against the sterile gut nonsense that is perpetuated here, but it is a rat study and it only lasted 8 weeks, so it's not really indicative of any outcome

Wops you are right, I got confused I read this New Study Funded: Towards reversing periodontal disease using Rapamycin at the same time, sorry about this misinformation. Please an admin remove the tootpaste from the title and change it to "Oral rapamycin" or something like that

Probably rapamycin got absorbed through the gut into the circulation I'm thinking.
We know it kills some fungi and modulates or interacts with immune system. Who knows, no proof of mechanism of action is given. Better to remain unbiased.
The authors mentioned that oral microbiome was changed.

 

[SaltiestSardine]

How? i dont understand that conclusion. one could spin it the other way around and say it is a argument for a "sterile" gut (assuming it was possible) just aswell. More likely however could it be that fungal infections are far more at the heart of diseases then is believed/acknowledged.

Then you never read the study, as its pretty clear that is what they are angling towards caused the effect

 

[TruffleGnocchi]

Then you never read the study, as its pretty clear that is what they are angling towards caused the effect

Your username suits you well.


You are welcome:

But there are still unanswered questions about how rapamycin affects the mouth as it ages. These include how the drug works at a molecular level

Interventions that target specific aging hallmarks have been shown to delay or prevent age-related disorders and extend lifespan in model organisms (Kaeberlein et al., 2015). Rapamycin, an FDA-approved drug, which directly inhibits the mechanistic target of rapamycin complex I (mTORC1), is one such intervention that extends lifespan and ameliorates a variety of age-related phenotypes.
Initial indications suggest that mTORC1 inhibition may also reverse declines in age-related heart function in companion dogs (Urfer et al., 2017a; Urfer et al., 2017b), and age-related immune function (Mannick et al., 2014; Mannick et al., 2018) and skin aging
Given that periodontal disease shows a similar age-related risk profile as other age-associated diseases (An et al., 2018), we predicted that interventions which target biological aging could be effective at treating periodontal disease. Consistent with that hypothesis, aged mice treated with rapamycin have greater levels of periodontal bone than control animals (An et al., 2017). In order to further test this idea and to understand potential mechanisms by which mTOR activity influences oral health during aging, we carried out a longitudinal study in which we asked whether transient rapamycin treatment during middle age can impact three clinically defining features of periodontal disease: loss of periodontal bone, inflammation of periodontal tissues, and pathogenic changes to the microbiome.

RANKL:OPG ratio and TRAP+ cell count:

Consistent with bone loss during aging, we detected significantly greater levels of RANKL in old animals of both cohorts compared to young animals (Figure 3A and B). OPG levels remained relatively stable, resulting in an increase in the RANKL:OPG ratio indicative of bone resorption exceeding bone formation (Figure 3C). These age-associated defects in bone homeostasis were suppressed by eight weeks of rapamycin treatment (Figure 3). In addition to increased RANKL:OPG ratio, a significant increase in TRAP+ cells was also observed in periodontal bone with age (Figure 3D and E). TRAP (tartrate-resistant acid phosphatase) is a histochemical marker of bone resorbing osteoclasts (Hayman, 2008; Ballanti et al., 1997). Rapamycin treatment for eight weeks also decreased TRAP+ cells. Together, our data indicate that rapamycin reverses periodontal bone loss in the aging murine oral cavity at least in part through inhibition of bone resorption.

In both the gingival tissue and periodontal bone, there was an increase in p65 expression with corresponding decrease of IκBα levels, indicating an age-associated increase in NF-κB inflammatory signaling in the periodontium.
Eight weeks of rapamycin treatment was sufficient to reverse these changes. We also examined the levels of inflammatory cytokines in the oral cavity associated with normative aging and rapamycin treatment in mice. Consistent with the increase in NF-κB signaling, we found elevated expression of several cytokines in both the gingival tissue and the periodontal bone (Figure 4, E and F). Eight weeks of rapamycin treatment reversed most age-associated chemokine and cytokine changes in both the gingival tissue and periodontal bone. Thus, transient treatment with rapamycin during middle-age can largely restore a youthful inflammatory state in both the gingiva and periodontal bone of mice.

Dont know what this points to other than Rapamycin treatment reduces the amount of Bacteroidetes bacteria to an amount seen in young mice or lower. Not sure how this goes against the sterile gut idea at all. If anything it supports it, but thats a stretch, since only Bacteroidetes species reduction is mentioned:

Dysbiotic shifts in the oral microbiome are thought to play a significant role in the progression of periodontal disease in humans. We and others have previously shown that rapamycin treatment can remodel the gut microbiome in mice (Bitto et al., 2016; Jung et al., 2016; Hurez et al., 2015); however, the effect of rapamycin on the oral microbiome has not been explored. Therefore, we sought to evaluate effects of rapamycin on the aged oral microbiome using 16S rRNA gene sequencing and Amplicon Sequence Variant (ASV) analysis approach. Examination of the alpha diversity of the oral cavity illustrated a significant increase in species richness during aging that rapamycin attenuated (Figure 5A, Figure 5—figure supplement 1). Among the most notable alterations in taxonomic abundance between groups was the reduction of Bacteroidetes phylum in the rapamycin-treated old animals (Figure 5B). When pooled across sites, no significant difference was observed between levels of Bacteroidetes in untreated young animals and old animals treated with rapamycin. Old animals treated with rapamycin in the JAX cohort had even lower levels of Bacteroidetes than young untreated mice (p<0.05), whereas in the UW cohort rapamycin treatment lowered the levels of Bacteroidetes to the level of the young mice (Figure 5—figure supplement 2). The Bacteroidetes phylum consists of over 7000 different species (Thomas et al., 2011) and includes bacteria associated with human periodontal disease such as Porphyromonas gingivalis, Treponema denticola, and Bacteroides forsythus.
This observation is further supported when analysis of the samples is performed independently by facility (UW-NIA or JAX) (Figure 5—figure supplement 3). Despite differences in animal facility and diet composition, no batch effect was detected when comparing the JAX and NIA-UW cohorts (PERMANOVA, nperm = 999, p=0.34) (Figure 5—figure supplement 4).

Their theory:

This adds further support for the Geroscience Hypothesis, which posits that any intervention which targets the biological aging process will simultaneously delay multiple age-related diseases and functional declines.
To the best of our knowledge, this is the first report of rejuvenation in the aged oral cavity.
One such question is whether the effects of rapamycin on the aged periodontium will persist after the treatment period or will rapidly revert back to the aged state. Improvements in age-related cardiac function associated with a similar rapamycin treatment regimen have been found to persist for at least eight weeks following cessation of treatment (Quarles et al., 2020), and it will be of interest to determine whether similar outcomes are observed for improvements in oral health.
It will also be important in future studies to determine whether these effects are mediated through local inhibition of mTORC1 in the gingiva and periodontal bone or through systemic effects on immune function or other tissues. Likewise, it will be of interest to understand whether additional features of oral health that are known to decline with age, such as salivary function, are improved by rapamycin treatment. Finally, these results suggest the intriguing likelihood that additional geroscience interventions, such clearance of senescent cells, may phenocopy the effects of rapamycin in this context. Such interventions could pave the way for the first effective treatments to reverse periodontal disease and improve oral health in the elderly.

Ben says it could be from anti-fungal effect since rapamycin is an anti-fungal.

A gero-scientist on twitter says it could be from immuno-suppresion, since rapamycin is an immunosuppresant. (and study mentions cytokines and other signaling molecules were reduced in rapamycin group).

The scientist say, I quote: "This adds further support for the Geroscience Hypothesis, which posits that any intervention which targets the biological aging process will simultaneously delay multiple age-related diseases and functional declines. "

You think it proves sterile gut idea is nonsense.. based on...?

I think maybe they think inhibiting mTOR reverses aging and since rapamycin inhibits mTOR this study supports that idea.
I think better to stay unbiased to not produce cognitive biases. That is a hinder to progress