Key Points:
- A metabolite from intestinal bacteria—phenylacetylglutamine (PAGln)—accumulates with age in the blood of humans.
- Injecting young mice with PAGln increases senescent cells, yet the blood pressure medication carvedilol and the senolytic ABT-263 lower senescent cell abundance.
- Data from the study suggest that carvedilol counteracts PAGln-induced senescence by blocking DNA damage, while the senolytic ABT-263 selectively eliminates senescent cells.
Published in Nature Aging, Zhao and colleagues from Fudan University in China show that a metabolite, PAGln, from gut bacteria accumulates with age in the blood of humans. Interestingly, injecting young mice with PAGln increases the abundance of proteins associated with senescent cells, providing evidence that the metabolite increases levels of senescent cells in tissues. Moreover, administering the blood pressure medication carvedilol or the senolytic agent ABT-263 attenuates cell senescence. These findings suggest that an age-related change in the composition of gut bacteria induces cellular senescence—a key hallmark of aging—possibly contributing to the processes of aging.
Additionally, the researchers found that PAGln degrades the cell powerhouse (mitochondria) and induces DNA damage by activating a protein called AMPK in human cells. Furthermore, the blood pressure medication propranolol blocks receptors called ꞵ-adrenoreceptors—cell receptors that play a role in the body’s fight-or-flight-response—to inhibit AMPK pathway-induced mitochondrial degradation and DNA damage. The senolytic agent ABT-263, on the other hand, selectively eliminates senescent cells that accumulate due to the effects of PAGln. Accordingly, the study’s data suggest that ꞵ-receptor blocking blood pressure medications combined with senolytic agents may work together for longevity-promoting purposes.
Disentangling How Age-Related Changes to Gut Microbes Modulate Aging
The findings from Zhao and colleagues support the notion that changes arising from an aging gut, such as an increased abundance of certain gut microbe species, may drive aging. Their study dissects the molecular pathway whereby a bacterial metabolite, PAGln, accumulates and stimulates the AMPK enzyme. AMPK stimulation then increases molecules, damaging to cells, called reactive oxygen species, which degrade mitochondria and damage DNA. The study’s data then provides evidence that this sequence of events induces cellular senescence, which blood pressure medicines and senolytics can alleviate, providing a possible means to counteract aging processes arising from age-related changes to gut bacteria.
The PAGln Gut Metabolite Increases with Age and Induces Cellular Senescence
Changes to gut bacterial composition, such as reduced diversity of gut bacterial species, have been correlated with aging, leading some researchers to posit that these changes may contribute to aging. However, evidence for a causative influence of gut bacterial changes has remained scarce. For this reason, Zhao and colleagues measured metabolites produced by gut bacteria in the blood of adults between the ages of 22 and 104. They found that one in particular, PAGln, showed a significant correlational increase with age.
Next, to find how PAGln affects signs of cellular aging, Zhao and colleagues measured markers for DNA damage and mitochondrial dysfunction in human cells. They found that PAGln treatment increased protein markers of DNA damage and dysfunctional mitochondria. Intriguingly, when they applied an inhibitor of AMPK—an enzyme linked to processes of aging—called compound C, markers of mitochondrial dysfunction and DNA damage fell, suggesting PAGln stimulates AMPK to initiate mitochondrial and DNA damage.
In addition to these findings, since ꞵ-adrenoreceptors activate AMPK, Zhao and colleagues tested whether the ꞵ-adrenoreceptor blocker and blood pressure medicine propranolol alleviated PAGln’s age-promoting effects in human cells. They found that propranolol reduced markers of mitochondrial dysfunction and DNA damage when applied with PAGln. These findings support that PAGln induces mitochondrial dysfunction and DNA damage, two contributors to cellular senescence, via AMPK activation.
Given the evidence that gut PAGln accumulation with age activates AMPK to induce senescence-related effects like DNA damage, Zhao and colleagues turned to mice to test whether increasing the bacterial metabolite PAGln induces senescence. Not only did they find that injecting young mice with PAGln increased kidney senescence but they also found that PAGln treatment induced kidney injury and lung scarring (fibrosis). These findings suggest that PAGln initiates cellular senescence, a hallmark of aging, and subsequent organ damage.
To confirm that PAGln-induced AMPK activation induces senescence, Zhao and colleagues tested whether the senolytic agent ABT-263 alleviates cellular senescence in young, PAGln-treated mice. They found, as expected, that ABT-263 reduced markers of cellular senescence in the kidneys of these mice, supporting that PAGln accumulation triggers cell senescence.
Zhao and colleagues also sought to find whether blocking AMPK activation with the ꞵ-receptor blocker and blood pressure medication carvedilol reduces cellular senescence. Indeed, they found that carvedilol reduced markers of senescence in the kidneys of PAGln-treated mice, confirming that AMPK inhibition with blood pressure medication alleviates cell senescence. These findings suggest that blood pressure medications like carvedilol can attenuate cellular senescence and possibly promote longevity.
Lifespan Studies in Animal Models Needed
Limitations to the study include that Zhao and colleagues did not complete any assessments of whether the blood pressure medications or the senolytic ABT-263 positively influences lifespan. In that sense, it would be interesting to find out whether propranolol, carvedilol, or ABT-263 increases the average lifespan in mice. If so, this would lend support to the idea that it may also help promote longevity for humans.
Nonetheless, the study provides a first glimpse of how changes to the gut bacterial composition with age may drive cellular senescence and ultimately aging. As such, it may be possible for future aging intervention therapeutics to target PAGln or to reduce gut bacteria associated with the PAGln metabolite.
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