Senescence, Aging…and the Microbiome: Part 1

Yesterday evening, I read about a study[i] done by scientists at the University of Salford, in Manchester, UK, that fascinated me enough that it sent me into one of my I-can’t-stop-reading jags.

First, a brief explanation:  senescent cells are old cells that have lost the ability to divide.  Once a cell enters senescence, it pumps out hundreds of proteins including chemicals to stop itself from dying. So these cells are not dead – but they are also not quite alive. They do serve several beneficial purposes, which I may go into at a later time, but for the moment, the important thing to know is that these “zombie” cells are known to lead to aging.  By killing off senescent cells, you can stimulate natural repair mechanisms in tissue.  Senescent cells are associated with many aging-associated diseases: cancer, heart disease, obesity, diabetes, infections, bowel diseases, autoimmune diseases,  dementia, and more.

A 2017 article in Scientific America[ii] gives a great summary of current research:  “…dozens of experiments have confirmed that senescent cells accumulate in ageing organs, and that eliminating them can alleviate, or even prevent, certain illnesses…This year alone, clearing the cells in mice has been shown to restore fitness, fur density and kidney function. It has also improved lung disease and even mended damaged cartilage. And in a 2016 study, it seemed to extend the lifespan of normally ageing mice.”

Substances that kill off senescent cells are called senolytics, and the hope is that these will be able to slow down or stop diseases associated with aging.

Several pharmaceutical agents have been shown to be senolytic, as has quercetin, a natural plant flavonoid (found in foods like onions, apples, green tea, for example). This “clearing out” of senescent cells only needs to be done periodically – kind of like a spring cleaning – to prevent disease.  Back to the University of Salford research:  these scientists discovered that ordinary Azithromycin (commonly known as Zithromax, and dispensed frequently as a Z-pack) is an incredibly effective sonolytic.  A single (low) dose of Azithromycin “…was shown to effectively kill and eliminate the senescent cells, with an efficiency of 97 percent.”  Healthy cells remained untouched.

Call me crazy, but I am all for keeping age-related diseases at bay,  and so, I continued to read.  I was pretty sure I’d read the term senescence in relation to the microbiome.  I looked back at  articles I’d read in the last 6 months or so and it turned out that I was right – it was from this past June  in the journal Nutrition and Healthy Aging.[iii]

The article has so much great information in it that it will require a second post.  I’ll cover the “what you can do about it now” information in my next post.  I’ll just conclude today with a general description of the relationship of senescent cells to the human biome.

Firstly, as usual, we don’t know nearly enough.  However, the general theory is that age-related microbiome changes (the decrease of beneficial flora like bifidobaceria and lactobacilli and the increase in opportunistic organisms like C. difficile (and thus, a decrease in anti-inflammatory short-chain fatty acids)) lead to an increase in permeability of the gut barrier (i.e. leaky gut).  This, in turn, leads to systemic inflammation as I’ve discussed in previous posts, which – in the case of aging, is known as inflammaging…which leads to age-related illnesses.  Whether or not these gut biome alterations directly lead to immune-system senescence is unknown.  It is possible that immune-system senescence leads to the biome alterations and inflammation. However, several studies have correlated the loss of microbiome diversity in aging adults (from increased use of drugs as we age, a life-time of antibiotic exposure, dietary modifications, constipation and so forth) with old-age frailty.  I am keeping an open mind but will not be at all surprised if this starts with biome depletion.

After all – given that the biome directly interacts with and affects the nervous system of the gut (the enteric nervous system (ENS)), it is very likely that the gut flora and fauna play a huge role in the functioning of the gut.  And the evidence we now have points to a “…correlation between host aging and senescence-like phenotypic changes to the ENS.”

So to sum up for today, as we age, there are negative changes to biome diversity, with a decrease in good bacteria and an increase in bad.  This leads to a reduction in the production of anti-inflammatory byproducts and these two phenomena then lead to alterations in the permeability of the gut epithelial lining, negative alterations to the enteric nervous system, immune senescence, inflammaging and ultimately, chronic illness and frailty.

More on all this next post!

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[i] https://medicalxpress.com/news/2018-11-antibiotics-senescent-cells-ageing.html

[ii] https://www.scientificamerican.com/article/to-stay-young-kill-zombie-cells/

[iii] Nagpal, R, et. al.  Gut microbiome and aging: physiological and mechanistic insights.  Nutrition and Healthy Aging. 2018;4:267-285.