Aging goes hand in hand with a decline in lysosomes, the cell's recycling stations that need an acidic environment to function. Their acidification is managed by the V-ATPase, but its activity drops with age, and until now no natural molecule was known to activate it directly. At the same time, the composition of the gut microbiota is known to influence the rate of aging, yet the specific molecular signals from bacteria to host cells remained unclear. This work fills that gap by linking microbial peptidoglycan to lysosomal function.
The researchers began with the observation that aging worms accumulate undigested bacteria in their intestines, and that mice show a age-related decline in lysozyme, an enzyme that breaks down bacterial cell walls. They then added purified peptidoglycan to the food of worms and mice and measured lifespan and functional readouts. To uncover the mechanism, they used co-immunoprecipitation with mass spectrometry to find proteins that bind peptidoglycan, and confirmed the interactions by immunoprecipitation. V-ATPase activity was assessed by phosphate release, and lysosomal acidification was tracked with pH-sensitive dyes.
Peptidoglycan supplementation extended median lifespan by 10% in worms and by 9.7–11% in mice, depending on sex, with maximum lifespan increasing even more (up to 21% in males). Older animals showed improved mobility, grip strength, and coat condition. Peptidoglycan localized to lysosomes and enhanced their acidification, while in cells it boosted the activity of cathepsins, the lysosomal enzymes. Mass spectrometry revealed direct binding of peptidoglycan to subunits of the V1 domain of the V-ATPase, especially VHA-13/ATP6V1A. The V-ATPase inhibitor bafilomycin A1 completely abolished the effect, and in worms with a mutation in the vha-12 subunit, peptidoglycan did not extend lifespan.
This work shows for the first time that a structural component of the bacterial cell wall acts as a direct activator of the lysosomal proton pump in eukaryotes. It broadens our understanding of the microbiota's role: bacteria are not only a source of metabolites or immune stimuli, but also suppliers of molecules that support intracellular infrastructure. The discovery of a gut–lysosome axis explains why an age-related decline in lysozyme can affect aging in distant tissues, and makes peptidoglycan the first natural V-ATPase agonist with geroprotective potential.
The next steps include identifying the minimal active fragment of peptidoglycan and solving the structure of its complex with the V-ATPase, possibly using cryo-electron microscopy. It will be necessary to map the tissue specificity of uptake and effects, and to explore connections with known longevity pathways (mTOR, AMPK). Testing the tolerability and efficacy of peptidoglycan in humans is a promising avenue that could lead to a new class of geroprotectors based on bacterial components.
The results could influence the development of anti-aging interventions, strategies for maintaining gut health, and approaches to treating lysosomal dysfunction in neurodegenerative diseases.
It is necessary to determine which peptidoglycan fragments are active and to test whether oral intake of peptidoglycan raises the level of N-acetylmuramic acid in human blood and improves lysosomal function.
The work links age-related decline in lysosomal function to a lack of microbial signal, opening a new approach to the problem of lysosomal dysfunction in aging and age-related diseases. It remains unclear how universal this mechanism is across tissues and species, and how it interacts with other pathways that regulate longevity.
Peptidoglycan is the very molecule that makes up the bacterial cell wall, and it is what our innate immune receptors recognize to trigger inflammation. Now it turns out that the same molecule can act as a molecular tonic for lysosomes.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.