Upregulation of Autophagy Reverses Age-Related Decline of Memory B Cell Function

Memory B cells undertake some of the more important tasks in coordination of an effective immune response, circulating in the body to accelerate the deployment of other resources in the immune system to tackle a specific threat. Dysfunction in B cells is a significant component of the onset of age-related immunosenescence, the progressively greater incapacity of the immune system. Selectively removing and replacing B cells has been shown to improve matters, but here researchers identify failing autophagy as an important factor. B cells are long-lived, and long-lived cells tend to build up metabolic waste that is resilient to the enzymes available to break it down. This gums up the structures and systems used in autophagy, causing it to fail, and the cells to thus become ever more cluttered with damaged protein machinery and other harmful waste. This in turn degrades function.

During a regular influenza season, about 90% of the deaths occur in people older than 65 years. Immune responses to vaccines are known to be particularly ineffective in the elderly population. A major correlate of protection for vaccinations is the specific antibody titer generated by long-lived plasma B cells. With a lifespan of several decades, long-lived lymphocytes are particularly prone to accumulation of intracellular waste. Autophagy recycles unwanted cytoplasmic material. Autophagy-deficient lymphocytes are unable to generate adequate responses, in particular long-lived lymphocytes, memory T cells, memory B cells, and plasma B cells.

Here we show that reduced autophagy is a central molecular mechanism underlying immune senescence. Autophagy levels are specifically reduced in mature lymphocytes, leading to compromised memory B cell responses in old individuals. Spermidine, an endogenous polyamine metabolite, induces autophagy in vivo and rejuvenates memory B cell responses. Mechanistically, spermidine post-translationally modifies the translation factor eIF5A, which is essential for the synthesis of the autophagy transcription factor TFEB. Spermidine is depleted in the elderly, leading to reduced TFEB expression and autophagy. Spermidine supplementation restored this pathway and improved the responses of old human B cells. Taken together, our results reveal an unexpected autophagy regulatory mechanism mediated by eIF5A at the translational level, which can be harnessed to reverse immune senescence in humans.

Link: https://doi.org/10.1016/j.molcel.2019.08.005

Comments

I begin to wonder if the universe/evolution doesn't want us to live forever. A ghost crab evolved to grow teeth in it's stomach to deter predators by growling when its hands are tied up.

Humans would have evolved to live forever and be immortal if it was intended correct? However, we are the only known species to learn, develop and innovate to make ourselves more efficient and adapt.

Such a conundrum...

Posted by: Peson1234 at September 11th, 2019 9:34 AM

I think the "universe/evolution" is neutral about indefinite lifespans.

Posted by: Quinn at September 11th, 2019 9:47 AM

@Quinn "I think the "universe/evolution" is neutral about indefinite lifespans."

Yet, evolution finds a way to make the changes it chooses. I hope you are correct though. Like I said, a lot of unknowns.

Posted by: Peson1234 at September 11th, 2019 9:53 AM

You may enjoy Cracking the Aging Code by Josh Mitteldorf. It makes an argument that short lifespans are actually selected for by evolution (and that a given max lifespan is an adaptive trait for a given species). He, nevertheless, is a believer that aging is malleable (see: wide range of natural lifespans among species) and interventions to extend this max lifespan are plausible. So, if you subscribe to the programmed aging hypothesis, perhaps all is not lost... if we can modify the program.

Posted by: Will at September 11th, 2019 10:47 AM

Does anyone know if any of the currently available senolytics cross the blood|brain barrier? DQ? Fisentin ideally (which I take)?

Posted by: Tom Schaefer at September 11th, 2019 12:16 PM

@Peson1234
Don't forget that we are still evolving. With over 7 billion people there is a lot of room for genetic change. However, the biological evolution in humans is a distant second to the terminological changes we can achieve in just a couple of generations. Basically a blink in evolutionary timescale.

Posted by: Cuberat at September 11th, 2019 2:29 PM

@Tom Schaefer
It should as it is a small molecule.

Posted by: Cuberat at September 11th, 2019 2:30 PM

@Will: Theories of programmed aging don't seem very compelling, at least in humans in terms of what they predict(ed) the underlying biochemistry of aging must look like; there's plenty of evidence of accumulating metabolic waste products, but not much of an evolutionary "kill switch". To make programmed aging work now you kind of have to concede that the most plausible trigger for such pathways to become active (or for maintenance pathways to be shut down to facilitate the organism's death) is accumulated, unresolved metabolic damage.

The evolutionary argument for programmatic aging is far stronger than the case from observed evidence, and I find the case that a given species may have an optimal lifespan in addition to selection pressure for early life advantages which are detrimental later in life quite compelling, but I think it's no longer possible to completely cut damage out of the equation.

Posted by: Dylan Mah at September 12th, 2019 2:36 PM

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