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Can flicking a molecular switch restore the aging immune system’s competence?

With age comes wisdom: mostly true. But a new study helps explain why one part of us - our immune system - gets decidedly dumber with age.

The aphorism "with age comes wisdom" is mostly true. But a new study in Cell Reports by Stanford immunologists Jorg Goronzy, MD, Connie Weyand, MD, and their colleagues here and at Emory University helps explain why one part of us —  our immune system — gets decidedly dumber with age.

I'm not saying the older we get, the smarter we get. A few moments spent watching a two-year-old picking up language skills quickly snuffs that notion. What I will say is that, barring dementia or crippling emotional trauma, the older we get the wiser we get. With time, we rack up an ever-richer collection of recalled experiences and outcomes. What we lose in cognitive speed, we gain in judgment.

In their later years, though, people's immune systems can start to resemble a crotchety, irritable and hyper-opinionated yet at the same time befuddled, perceptually challenged and forgetful old codger. While there's substantial variation among individuals, the average aging immune system is increasingly apt to fire off feeble, poorly timed and misdirected sprays of shotgun pellets rather than the forceful, well-aimed bullets of our youth. (I described this phenomenon, called "inflammaging,"in a Stanford Medicine article a couple of years ago.)

As a result, older people fall prone to a long list of diseases — from cancer to autoimmunity, from shingles to type-2 diabetes — while becoming less competent at fighting off infectious pathogens. Adding insult to injury, many older people's immune systems respond poorly to vaccination, so they're less capable of preventing infection in the first place.

There are probably many reasons for this. Here's one of them.

Patrolling immune cells known as T cells respond to the sighting of a foreign invader (or to potentially cancerous cells) by firing up their engines, dividing serially into much-expanded teams, and differentiating into various categories of military expertise: Many become short-lived "warrior" cells dedicated to destroying viral, bacterial, fungal or parasitic interlopers or fifth-column nascent cancer cells. But it's important that some of those T cells differentiate into long-lived "memory" cells that recall previous encounters and can speed up or call off the immune response as the situation merits.

A big factor in the decision a young T cell makes to become either a fighter or a historian is the relative abundance, within that cell, of a small, regulatory microRNA molecule called MiR-21 that acts as a switch, promoting some intracellular processes while inhibiting others. Goronzy, Weyand and their peers found that this molecular switch is more abundant in older people's T cells, and that this causes fewer T cells to differentiate into memory cells.

Power without intelligence makes for lots of bad calls. You fight the wrong battles in the wrong place with the wrong enemies — sometimes you even attack your own healthy tissues.

MiR-21 inhibiting drugs are now being developed for unrelated clinical uses. Such medications, the scientists speculate, may prove able to override the age-related increase in MiR-21 abundance within T cells, restoring memory-mediated moderation to the body's defense structure.

Photo by Dean Hochman

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