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Fasting or beta-hydroxybutyrate administration reduces cellular senescence.

Beta-hydroxybutyrate (BHB) is a ketone produced by the body during times of carbohydrate scarcity such as those encountered while practicing a ketogenic diet, fasting, or exercise, which have all demonstrated the ability to extend healthspan and lifespan. However, the precise effects of beta-hydroxybutyrate on the cellular mechanisms of aging are not well understood. Findings of one report show that BHB administration and fasting both reduce senescence in mice.

Senescence occurs when a damaged cell terminates its normal cycles of growth and reproduction for the purpose of preventing the accumulation of damaged DNA or mitochondria. While senescence plays a vital role in human development and wound healing, the accumulation of senescent cells is associated with diseases of aging such as Alzheimer’s disease, Parkinson’s disease, cardiovascular disease, type 2 diabetes, and glaucoma. Lifestyle habits or drugs that increase beta-hydroxybutyrate may extend healthspan and reduce disease risk by slowing the rate of senescence.

The researchers conducted an experiment that involved culturing human vascular endothelial (i.e., blood vessel cells) from the umbilical cord and aorta, followed by an experiment with mice. To compare the effects of BHB supplementation and fasting, the researchers fed one group of mice a normal diet, then randomly assigned them to receive an injection of BHB or a placebo after they had fasted for just five hours. Using a second group of mice, the researchers randomly assigned half of the group to fast for 72 hours and the other half to eat normally. In both the cell culture and mice experiments, the researchers measured changes in gene expression and metabolic activity.

The researchers found that BHB reduced senescence in vascular cells due to increased expression of the transcription factor Oct4, which is a protein that binds to DNA and regulates cell regeneration and stem cell differentiation. Compared to mice who received a placebo injection, mice who received BHB had reduced senescence in vascular cells through the same Oct4 pathway as in cell culture. Mice who fasted also robustly activated Oct4, leading to activation of senescence-associated markers such as mTOR inhibition and AMPK activation, two pathways that modulate lifespan.

Prior to this study, it was not known whether Oct4 was active in adult cells; however, these results show fasting or BHB administration activates youth-associated DNA factors that reduce senescence in mice and cell culture. Future studies are needed to translate these results into relevant use for humans because humans have very different nutritional needs than mice to cells in culture.

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    Is there any indication what minimum level of beta-hydroxybutyrate would be necessary for this protection. That is could this be achieved by just taking a couple of grams of an exongenous beta-hydroxybutyrate salt.

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      @woody42, not really. My take was >2nM might reach the therapeutic range. But that is pure speculation on my part. I’m doubting most people can get to >2nM just taking a couple of grams of exogenous BHB-salt. But it would depend on what your diet, etc. were like otherwise.

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      From the paper: “Cellular quiescence is a crucial process for maintaining the stemness of embryonic stem cells (ESCs) through inducing autophagy. We did not show sufficient results to prove β-HB induces autophagy and autophagy-dependent cellular quiescence (An et al., 2014, García-Prat et al., 2016). However, we predict that β-HB can induce autophagy in vascular cells, as well as ESCs, based on our observations of AMPK activation and mTOR inhibition by Oct4 upregulation after treating with β-HB in vascular cells. ”

      @rhonda – is this enough to make you consider a ketogenic diet? Since I started ~8 hour TRE, I have no difficulty maintaining >2mM BHB fasted most mornings of the week.

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        I’m considering experimenting a modified ketogenic-ish diet with an emphasis on salmon, avocado, olive oil, nuts…as long as I can eat a lot of leafy greens and some blueberries.

        I also seem to have no problem getting high levels of BHB with a 16-hour fast.

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          What concentration of blood BHB do you get after a 16-hour fast?

          Leafy greens don’t seem to be an issue for me. I’m eating 2 large salads a day sometimes. I put lots of a salad dressing I make myself on them–just “O-live” olive oil (~80%), Braggs ACV (~20%), sweetened with some raspberry stevia.