Berberine as an mTOR Inhibitor that Reduces Generation of Senescent Cells and Extends Life Span in Mice
Today's open access paper is an interesting look at berberine as an mTOR inhibitor and its effects on cellular senescence in cell culture and animal models. This is particularly interesting in the context of recent work on rapamycin, showing low doses to reduce the burden of cellular senescence in aged skin. In both cases this appears to be the result of reducing the pace at which cells become senescent, allowing natural clearance mechanisms to catch up - though there is always the question of whether or not the various protein markers used to identify senescence are reduced because the number of senescent cells are reduced, or are reduced because the drug causes a lowering of expression of these proteins.
Is it a good idea to prevent cells from becoming senescent? Cellular senescence halts replication and encourages programmed cell death or destruction via the immune system. It is way to remove damaged and potentially damaged cells from tissues. If a method of preventing senescence gives cells a chance to repair themselves, then fine, but otherwise it starts to sound like a way to increase cancer risk - to have damaged cells remain active while damaged. To refute that proposition, one has to run life span studies, as the researchers did here. Clearly, in these mice, preventing entry into senescence is beneficial, since it increases life span. This may again be a matter of allowing natural clearance processes a chance to catch up and reduce the overall level of cellular senescence. Or it may be that the harmful inflammatory signals produced by senescent cells are, on balance, far worse that the raised cancer risk resulting from prevention of senescence.
Studies of this nature must lead us to think about the right dosing schedule for senolytic therapies capable of destroying senescent cells. If natural clearance of senescent cells is taking place in late life, and accumulation is a matter of too much creation versus a slowed pace of clearance, then senolytic treatments should be delivered every few months. If, on the other hand, accumulation is a matter of a small fraction of all senescent cells managing to linger for years or more, senolytic treatments can be much less frequent. At present there is all too little evidence, but the evidence that does exist suggests that the former scenario is more likely.
Cellular senescence is one of the most important in vivo mechanisms related to aging. Senescent cells impair tissue function by irreparable cell damage resulting from acute stress or natural aging, consequently restricting the lifespan. Cellular senescence can be categorized into two groups. The replicative senescence, seen after approximately sixty rounds of cell division in cultures (the Hayflick limit), results from the progressive erosion of telomeres following each cell division. This progressive erosion leads to telomere dysfunction and irreversible cell-cycle arrest.
The second category is defined as premature cellular senescence. It is unrelated to telomere shortening but is related to persistent cellular stress. Thus, replicative stress caused by oxidative DNA damage, activation of oncogenes, and loss of tumor suppressor genes also results in premature senescence. Furthermore, premature senescence includes irreversible impairment of tumor cell reproductive capability via chemotherapy or radiotherapy-induced apoptosis which is defined as a drug or radiation-induced senescence. The in vivo stress-induced premature senescence of normal cells is considered to be a critical mechanism affecting organismal aging and longevity.
Berberine (BBR), a natural alkaloid found in Coptis chinensis, has a long history of medicinal use. Furthermore, BBR possesses anti-cancer, anti-inflammatory, and anti-neurodegenerative properties. Although the biological properties of BBR are well-documented, there is little evidence of its role in anti-aging processes. It was previously observed that BBR inhibited mTOR/S6 signaling concurrent with the reduction in the level of endogenous oxidants and constitutive DNA damage response. Thus, it was hypothesized that BBR, with its potential anti-aging effects, could treat the senescence in aging cells.
This study presents the effects of berberine (BBR) on the aging process resulting in a promising extension of lifespan in model organisms. BBR extended the replicative lifespan, improved the morphology, and boosted rejuvenation markers of replicative senescence in human fetal lung diploid fibroblasts. BBR also rescued senescent cells with late population doubling (PD). Furthermore, the senescence-associated β-galactosidase (SA-β-gal)-positive cell rates of late PD cells grown in the BBR-containing medium were ~72% lower than those of control cells, and its morphology resembled that of young cells. Mechanistically, BBR improved cell growth and proliferation by promoting entry of cell cycles from the G0 or G1 phase to S/G2-M phase.
Most importantly, BBR extended the lifespan of chemotherapy-treated mice and naturally aged mice by ~52% and ~16.49%, respectively. The residual lifespan of the naturally aged mice was extended by 80%, from 85.5 days to 154 days. The oral administration of BBR in mice resulted in significantly improved health span, fur density, and behavioral activity. Therefore, BBR may be an ideal candidate for the development of an anti-aging medicine.