Intestinal stem cell aging at single-cell resolution: Transcriptional perturbations alter cell developmental trajectory reversed by gerotherapeutics
The intestinal epithelium consists of cells derived from continuously cycling Lgr5hi intestinal stem cells (Lgr5hi ISCs) that mature developmentally in an ordered fashion as the cells progress along the crypt-luminal axis. Perturbed function of Lgr5hi ISCs with aging is documented, but the consequent impact on overall mucosal homeostasis has not been defined. Using single-cell RNA sequencing, the progressive maturation of progeny was dissected in the mouse intestine, which revealed that transcriptional reprogramming with aging in Lgr5hi ISCs retarded the maturation of cells in their progression along the crypt-luminal axis. Importantly, treatment with metformin or rapamycin at a late stage of mouse lifespan reversed the effects of aging on the function of Lgr5hi ISCs and subsequent maturation of progenitors. The effects of metformin and rapamycin overlapped in reversing changes of transcriptional profiles but were also complementary, with metformin more efficient than rapamycin in correcting the developmental trajectory. Therefore, our data identify novel effects of aging on stem cells and the maturation of their daughter cells contributing to the decline of epithelial regeneration and the correction by geroprotectors.
Unfortunately, metformin causes gastrointestinal problems in 20 to 30% of patients. Sometimes it is relatively mild. I took metformin for decades and did not know metformin was causing GI problems until I stopped taking it. Since I stopped I feel much better with hardly any GI problems. Coupled with the fact that older people, as per your article, have more problems anyway, metformin might not be for everyone.
“Metformin causes GI intolerance in 20-30% of patients”
It’s possible that metformin increases longevity through mTORC1 inhibition the same as rapamycin but to a smaller extent. The problem is that continuous inhibition of mTORC1 blunts the effect of resistance training. I had muscle increases from going to the gym for years while taking metformin but I wonder how much more mass I would have obtained if I hadn’t been taking metformin.
I am now taking canagliflozin instead of metformin to keep my glucose levels low.
I do believe that taking rapamycin and metformin together might be redundant as they are both mTORC1 inhibitors.
“Metformin indirectly activates AMPK, a major mTORC1 inhibitory kinase”
“Thus, acute and/or chronic blunting of mTORC1 activation may contribute to the decreased lean mass gains in metformin-treated subjects.”
Regulation of hematopoietic stem cells differentiation, self-renewal, and quiescence through the mTOR signaling pathway
Hematopoietic stem cells (HSCs) are important for the hematopoietic system because they can self-renew to increase their number and differentiate into all the blood cells. At a steady state, most of the HSCs remain in quiescence to preserve their capacities and protect themselves from damage and exhaustive stress. However, when there are some emergencies, HSCs are activated to start their self-renewal and differentiation. The mTOR signaling pathway has been shown as an important signaling pathway that can regulate the differentiation, self-renewal, and quiescence of HSCs, and many types of molecules can regulate HSCs’ these three potentials by influencing the mTOR signaling pathway. Here we review how mTOR signaling pathway regulates HSCs three potentials, and introduce some molecules that can work as the regulator of HSCs’ these potentials through the mTOR signaling. Finally, we outline the clinical significance of studying the regulation of HSCs three potentials through the mTOR signaling pathway and make some predictions.
N=1. I took Metformin and Paxlovid while suffering from moderate COVID. Paxlovid immediately stopped COVID from getting any worse. I felt it established a wall that prevented COVID from progressing further. Also, I do not think I have long COVID for what it’s worth. If you get COVID, I recommend Paxlovid and Metformin.
Thursday I developed a cough, but I did a COVID test and it came back negative.
Friday I went to work, but at lunchtime I felt so terrible that I had to leave early and go home. I slept all Friday afternoon. I had alternating hot and cold chills but no fever.
Saturday I decided to test for COVID again, and it came back positive. I went to the hospital where I had a mild fever. They gave me Paxlovid (5 days). I checked into a hotel to isolate myself.
Sunday I stayed in the hotel and took my Paxlovid and Metformin along with antibiotics and some other hospital-prescribed meds (cough syrup, etc.).
I tested daily, and the lines on the COVID tests got fainter each day which signaled less and less of a viral load. Even after a week and finishing the Paxlovid, there was still a faint line on the COVID tests. I only had a cough at this point.
The cough persisted for another week. I only took my hospital-prescribed meds, Paxlovid and Metformin during this time.
That’s pretty much what happened.
Antibiotics wasn’t my choice. It was prescribed by the hospital doctor. I thought that since he prescribed it, I should take it. But I had the same question. I should have asked him why but I only found out when I picked up my meds at the hospital pharmacy.