Chapter 188
Changing Aging — 25
Another mitochondria-targeted drug that has completed early clinical trials activates adenosine monophosphate-activated protein kinase (AMPK, Cambrian Bio, ATX-304), the enzyme viewed as “the guardian of metabolism” and a key means of restoring mitochondrial function. The jury is still out.
We began this part of our discussion of antiaging with immune-enhancing approaches, so it is fitting we conclude with anti-inflammatory drugs. These drugs are beginning to be assessed in clinical trials. The GLP-1 family of drugs have been shown to improve various aging clocks in old mice at least as well as rapamycin, with particular impact on reversing the epigenetic clock of the hypothalamus. The ability to reduce the toll of age-related diseases affecting the heart and kidneys has already been shown, and there are encouraging data for potential disease-modifying benefit for Parkinson’s and ongoing clinical trials in Alzheimer’s disease. If it is proven beneficial for preventing or slowing the progression of neurodegenerative diseases, the suppression of brain inflammation by the GLP-1 drugs through the gut-brain axis, despite their lack of direct penetration across the blood-brain barrier, may turn out to be the fundamental mechanism. The company BioAge is assessing the combination of a GLP-1 drug and azelaprag (mimicking apelin, a muscle peptide that is reduced with aging) in a clinical trial for extending health span.
There are several other potent anti-inflammatory drugs that are candidates to modulate the aging process. Blocking the mitogen-activated protein (MAP) kinase (losmapimod) had a marked effect in skin of older adults for reducing inflammation while improving immune cell function. I’ve mentioned the promise of inhibiting the NLRP3 inflammasome. Another group of powerful inflammation blockers inhibit the cGAS-STING pathway (cyclic GMP-AMP synthase stimulator of interferon genesis), which has been implicated in inflammaging of the aged brain. Treatment with a cGAS-STING blocker in aged animal models markedly reduced inflammation in multiple tissues and restored innate immune cell function. Reversing fibrosis, the untoward organ scarring that can develop with aging, is being pursued in clinical trials with new drugs identified that also have strong anti-inflammatory action. Multiple other paths for reducing inflammation are being pursued, such as manipulating the gut microbiome.
The multiplicity and intensity of efforts underway to alter the human aging process, albeit still preliminary, are marvelous. Transforming aging isn’t going to be easy or accomplished with a silver bullet, but in the last chapter we’ll run through a path forward.