#1

A few weeks ago, I posted a paper to the effect that certain age related changes in the heart are actually an a beneficial adaptation, and attempting to revert those changes to a more youthful profile are actually counterproductive:

Per an interview conducted by Matt Kaeberlein with a microbiome researcher, the same appears true for the gut microbiome, where a less diverse biome of an older person is superior for the older person, and bringing it back to a more diverse youthful state is a health negative in the older person.

This is a very important concept. The body changes with age. Not all changes are negative and must be opposed. Some are adaptive and beneficial for the aging organism. Therefore blindly attempting to revert all age related changes is very dangerous.

It is critical to distinguish between negative changes that compromise health/lifespan, which it is good to fight against, and adaptive changes which should not be opposed. This is a question that one must ask of every intervention: is this going to help or hurt, not simply is this an age related change - is the change good or bad.

The same appears true of some aspects of the aging immune system.

Sustained immune youth risks autoimmune disease in the aging host

https://www.nature.com/articles/s43587-025-00919-w

“Immune responses underlying autoimmune diseases follow the same principles that protect individuals from infection and malignancies. However, while protective immunity wanes with progressive age, the risk for autoimmune disease steadily increases; incidence rates for many autoimmune diseases peak in later life. Here, we discuss whether aging predisposes to autoimmunity, arguing that disease progression in the autoimmune vasculitis giant cell arteritis is driven by age-inappropriate sustenance of immune competence. Stem-like memory CD4+ T cells (TSCM) that reside near the vasculitic lesions provide a continuous supply of pathogenic effector T cells. Antigen-presenting cells lacking inhibitory ligands further impede peripheral tolerance mechanisms. In the context of aging-associated accumulation of neoantigens, this incessant immune competence sets the stage for unopposed autoimmunity. We propose that sustained immune youthfulness can be detrimental to the aging host, while immune aging may be a beneficial adaptation to balance reactivity to self-antigens and non-self-antigens and thus protect from autoimmunity in aging.”

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#2

Meanwhile the immune system does age as it meets the challenges of the fallout from the aging process itself.

Immune surveillance of senescent cells in aging and disease

https://www.nature.com/articles/s43587-025-00910-5

“Senescent cells are intrinsically immunogenic and can be eliminated by the immune system to facilitate tissue repair and regeneration. However, immune-mediated elimination is compromised with age, causing senescent cell accumulation in tissues, thus limiting healthspan and lifespan and promoting age-related diseases such as cancer. Here, we review how different components of the innate and adaptive immune systems, including natural killer cells, macrophages, neutrophils, dendritic cells, T cells and B cells, target senescent cells and how the intrinsic properties of senescent cells can lead to their escape from surveillance. We also discuss the phenomenon of senescence in immune cells themselves and how this affects the surveillance of senescent and cancerous cells. Finally, we touch on emerging therapeutic strategies to enhance the immunosurveillance of senescent cells, as understanding the molecular basis of senescence immunosurveillance and why its potency fails during aging may offer opportunities to treat senescence-mediated age-associated diseases and tissue dysfunction.”

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#3

We see an increasingly understood role of the gut microbiome in immunity.
How exactly would one bring “
it back to a more diverse youthful state
”?

The gold standard, fecal transplants. via Cleveland Clinic: Fecal Transplant

But one can only get these legally in the US for C. diff infections (really dysbiosis) and that only after everything else fails.

A less diverse microbiome might have benefits (although I’d like to see research on this) but a “normal” or “healthy” old microbiome certainly wouldn’t include dysbiosis of bacteria like firmicutes.

We can successfully bio-hack around the margins. I discussed this across the forum.

A researcher making a statement about bringing back a more youthful state when readily available ways don’t exist to do so seems specious.

Even if readily possible, one would need to assess the risks of numerous immune system conditions, e.g.:

with what ever downside one would have from having a “young” microbiome.

#4

But that’s exactly what was done in mice. Fecal transplants. And doing young biome transplant to old mouse had negative consequences. Whereas the same swap with blood (young to old) had positive effects. Proof of concept. Shows up robustly in animal models. Unlikely to be the opposite in humans.

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#5

The issue here is whether you are intervening on the core aging pathway by resetting the development/aging clock or responding with systemic props to maintain the effectiveness at a later stage in the development/aging clock.

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#6

We see it in our work at Sapere Bio. Our algorithm that estimates immune resilience penalizes for having a more “youthful” gut at an older age. I’d say, the trend generally flips around 60yo.

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