The body produces all of these inflammatory signals to mobilize the immune system to clear damage out of the artery, and both the immune cells and the inflammation are protective in the short term. But the longer they fight a losing battle, the more they devolve into agents of destruction, like Kurtz and his men after too many years in the jungles of Apocalypse Now. So what to do about them? Administering drugs that block the signals that recruit immune cells to the artery would allow damaged lipoproteins to injure the arteries even more directly, and forcibly suppressing the inflammatory reaction would undermine the role of inflammation in the immune system and other functions.
This dilemma is illustrated by a major clinical trial in which doctors treated people who had previously suffered a heart attack with an antibody called canakinumab that directly and indirectly tamps down on inflammatory messenger-molecules. In one sense, the trial was a success: the high-risk subjects who received the antibody had a 15% reduction in future heart attacks compared to those who received placebo shots. Yet despite that seemingly life-saving benefit, canakinumab-treated subjects didn’t actually live any longer — because in shutting down the immune system’s inflammatory response, the antibody also increased the risk of deadly infections.
There’s a very similar story behind inflammation in the brain afflicted with neurodegenerative aging of the Alzheimer type (AD) and the activation of brain-resident immune cells called microglia. Microglia are like the brain’s macrophages: they gobble up particulate matter, cellular debris, and other harmful materials in the brain — including, importantly, beta-amyloid, the extracellular aggregate most closely linked with AD. This happens because beta-amyloid activates the complement system, which flips the switch on microglial surface receptors that push them from being agreeable neuronal housekeepers into beast mode. But with a rising burden of beta-amyloid and unresolved injury to the brain, microglia and the complement system eventually become toxic, killing neurons and warping and shriveling the connections between them.
Other common derangements of intercellular communication that begin as adaptations to cellular and molecular aging damage include when the body responds to insulin resistance by producing ever more insulin, creating a vicious cycle that culminates in type 2 diabetes; and the hormonal signals behind hot flashes, which result from the pituitary gland’s increasingly shrill attempts to stimulate the release of a faltering supply of eggs.
In addition to regulated shifts that the body initially made in order to maintain normal function as the burden of damage rises, aging also distorts signaling networks because of the direct effects of aging damage to cells and biomolecules. Examples include the hodgepodge of signaling factors, growth factors, and enzymes (SASP) spewed out of senescent cells and the systemic oxidative stress indirectly exported from cells overtaken by mitochondria bearing large DNA deletions (which distort the use of free radicals as a signaling system).
In a recent update of the Hallmarks, the authors of the original Hallmarks paper wrote “that the final hallmark that we listed in 2013, altered intercellular communication, was too vast, requiring a separate discussion of chronic inflammation and age-associated dysbiosis.” From the SENS perspective, however, even the original creation of a separate Hallmark for altered intercellular communications was redundant at best and a counterproductive distraction at worst — let alone splitting off a new Hallmark by drawing an arbitrary line between age-related chronic inflammation and other kinds of signaling changes with age.
Again: Dr. de Grey, the authors of the Hallmarks paper, and the majority of geroscientists (even those who use language that suggests otherwise) agree that altered intercellular communications in aging are downstream effects of primary aging damage. If we are to set up a structure to classify age changes that doubles as a battle plan for tackling aging, we should use a version of Occam’s Razor to slice through these secondary changes and cleave as close as possible to the “bones” of degenerative aging: the cellular and molecular damage that drive such changes in the first place.
To develop powerful and iterable longevity therapeutics and minimize side effects, changes in intercellular signaling with age should not be a target for intervention. What we said earlier about compensatory Hallmarks applies more broadly here: the proper target for longevity therapies is the damage that causes these signaling changes, not the signals themselves.
In this first of two posts, we’ve looked at the thinking behind the structural framework into which the Hallmarks are organized. In next month’s post, we’ll come back and look at each of the Hallmarks individually and see how well they line up with the SENS Seven — and when they don’t line up, or when they overlap with more than one of each other, we’ll ask why the two systems differ, and what might be missing or superfluous in either system.
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- Source: https://www.sens.org/hallmarks-aging-make-sens-part-1/