Altered Intercellular Communication: Hallmark of Aging #9

Altered intercellular communication is one of the twelve hallmarks of aging: the gradual breakdown in how cells signal to one another. As inflammation and cellular "noise" rise with age, those signals grow garbled, and that miscommunication becomes a driver of aging in its own right.

As he has grown older, my grandfather has slowly lost his hearing. He wears a pair of hearing aids now, which has given him a certain selective grace: he listens when he wishes to, and switches the aids off when a good book has his attention or the room grows too loud. Too many voices at once overwhelm him. It has quietly reshaped how he communicates with everyone around him.

Something not unlike this happens inside us as we age. Our cells do not choose to stop talking, but the conversation between them becomes deregulated, especially as inflammation and background "noise" rise. The coordinated signaling that keeps tissues healthy begins to falter.

How the Hallmarks Connect

In the original hallmarks of aging (2013), Lopez-Otin and colleagues folded inflammation into their final hallmark, altered intercellular communication. In the 2023 update, inflammation became a hallmark in its own right. All of the hallmarks are interrelated, each feeding the others, but inflammation and altered communication are especially hard to separate.

Inflammaging

Inflammaging is the low-grade, chronic inflammation that accompanies aging, a term coined by Salminen and colleagues. It arises from several sources at once: an immune system less able to clear pathogens and damaged host cells, the pro-inflammatory secretions of senescent cells (known as SASP), and a faltering autophagy response, itself another of the new hallmarks we will explore soon.

The inflammaged cell, if you will allow the coinage, produces more IL-1β, tumor necrosis factor, and interferons. Each adds to the "noise" in the system and erodes the body's ability to keep itself in balance.

Contagious Aging

Beyond inflammation, there is evidence that aging changes in one tissue can hasten deterioration in others, something Lopez-Otin called "contagious aging." Senescent cells can push neighboring cells into senescence, and the microenvironment they create can contribute to functional defects in CD4 T cells, the white blood cells that help launch the immune response to pathogens.

Clues in the Blood

Between the two hallmarks publications, researchers turned to the blood, another of the body's communication channels, in search of circulating factors that speed or slow aging.

The evidence is striking. Transfusing old blood into young mice induced features of aging, pointing to pro-aging factors in circulation, among them the chemokine CCL11 and the protein β2-microglobulin, which reduce the formation of new neurons; IL-6 and TGF-β, which impair the formation of blood components; and complement factor C1q, which hampers muscle repair. Several of these are secreted as part of SASP.

The reverse also held. Blood from young mice restored renewal and repair capacity in older mice, rejuvenating multiple tissues and reviving age-reduced gene expression. Researchers identified several rejuvenating factors, including ones acting on blood stem cells, on the hippocampus, and on endurance and whole-body metabolism. These findings come from mouse studies.

Long-Range and Short-Range Signals

The central nervous system, the brain and spinal cord, shapes many aspects of aging in the peripheral organs through what researchers call long-range communication. In mice, engineering the brain to overexpress genes like SIRT1, or to underexpress others like IKBKB, has extended lifespan. These and other soluble factors released from tissues such as fat also influence signaling between neighboring cells, the short-range channel. Here again, the system fills with noise, messaging that tells cells and systems to age.

The Extracellular Matrix

In the spaces between cells, the extracellular matrix, aging alters long-lived proteins through processes like collagen cross-linking, which can lead to tissue fibrosis. Driven by an excess of growth factors that switch on pro-fibrotic genes, this shows up as stiffness, and that rigidity affects the cells nearby, senescent cells especially. In response, those cells secrete still more factors, amplifying the damage and activating pro-senescent, pro-fibrotic, and pro-inflammatory pathways.

This rigidity has been causally linked with aging, and several studies point to possible avenues for healthier aging, such as activating the YAP gene in mice. Like the long- and short-range signaling examples, the stiffening matrix is another frontier in the search for healthy aging.

Why It Is an Integrative Hallmark

Like cellular senescence, altered intercellular communication is an integrative hallmark. Integrative hallmarks emerge when the damage caused by the primary and antagonistic hallmarks outpaces the cell's ability to restore balance. The "noise" generated by the other hallmarks, senescent cells and inflammation chief among them, breaks down communication, and that breakdown drives further deterioration of the cells that ultimately shape how we age.

Supporting Healthy Cell Communication

Because this hallmark is downstream of so many others, the most sensible way to support healthy cell communication is to support the upstream hallmarks that feed it, chiefly inflammation, senescence, and autophagy. Among the best-studied natural levers here are dietary restriction and food-derived spermidine, a calorie restriction mimetic that research links to multiple hallmarks of aging.

To understand how that works, see our guide to what spermidine is, how it lets you induce autophagy without fasting, and how spermine and spermidine work together as polyamines.

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This article is for educational purposes only and is not medical advice. Primeadine® is a food-derived supplement, not a treatment, cure, or preventive for any medical condition. Individual results vary. Consult a qualified healthcare provider before starting any supplement, particularly if you take medication or have a health condition.