Glucosepane

The remediation project: wanted, an enzyme that makes it let go

Breaking glucosepane is one of the clearest repair jobs in the biology of aging: an inert crosslink that piles up in long-lived collagen and that the body has no enzyme to remove. Glycation is the protein modification with no enzyme on either side: of the more than 600 known modifications, most are installed and removed by enzymes, but glycation has no 'writer', and whether humans have deglycases that broadly erase advanced glycation products is still disputed (Nat. Chem. Biol., 2025).

The first generation of 'AGE breakers' did not do it. The title of a 2003 paper says it all: 'AGE-breakers cleave model compounds, but do not break Maillard crosslinks in skin and tail collagen.' They cut sugar-derived alpha-diketone bridges, and glucosepane has none: it is a ring formed by water elimination. Later chemistry showed the best known of them works as a scavenger of reactive dicarbonyls, and a year-long study in healthy 70-year-olds found it did not reverse the vascular effects of decades of sedentary aging (Exp. Gerontol., 2013).

SENS Research Foundation made extracellular crosslinks one of its seven repair strands (the 'GlycoSENS' programme) and paid for the 2015 total synthesis, which finally gave researchers pure glucosepane to test against. That made antibodies (2020), a fluorescent aptamer stain (2025) and blood measurements possible. (LysoSENS, sometimes mentioned in the same breath, is a different strand: microbial enzymes against junk inside cells, such as lipofuscin; it proposed screening microbes for enzymes that eat the target. SENS Research Foundation merged into the Lifespan Research Institute in October 2024.)

A company spun out of the synthesis lab announced in 2020 that it had found bacterial enzymes that degrade glucosepane; no paper ever reported one. Its 2026 paper in Nature Communications evolved an enzyme from a bacterial glycine oxidase (five rounds of directed evolution, over 500 million variants, a starting point found by scanning 44,783 AlphaFold structures) that cut CML, a different sugar adduct, by roughly half or more in aged human lens, aorta and skin samples (45% in lens by mass spectrometry, over 70% in aorta and over 55% in skin sections), ex vivo, in homogenized protein or fixed sections, not in living tissue. The same paper says glucosepane 'is currently resistant to reversal'.

Two complications keep the case hard. Crosslinks slow the turnover that would otherwise replace damaged collagen, and some collagen is never replaced anyway: carbon-14 dating shows adult knee cartilage collagen has essentially no turnover, and the Achilles tendon's core is laid down in the first 17 years of life. And the catalogue isn't closed: crosslinks are more than 40% of all known advanced glycation end products, and a new one, the first arginine-arginine crosslink, was reported in 2026.