Researchers here argue that it was a mistake to omit from the hallmarks of aging of cross-links and other forms of persistent modification to extracellular matrix molecules. Cross-links degrade the elasticity and other structural properties of tissue, something that is concerning in skin and much more serious in blood vessels, as it contributes to hypertension and cardiovascular mortality. Cross-linking has, of course, long been prominent in the SENS outline of the causes of aging and how to best reverse them. The SENS Research Foundation funded academic work that led to the launch of Revel Pharmaceuticals, a company undertaking the clinical development of cross-link breaking enzymes targeting the most common form of persistent cross-link in humans, those involving glucosepane.

Aging is undoubtedly one of the most important and yet unsolved problems of humanity. Many theories have been put forward, but none have yet been fully verified. Modern geroscience enumerates nine hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. The proposed hallmarks are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. However, this list is missing one particularly important hallmark: stochastic non-enzymatic modification of long-lived macromolecules.

First proposed in 1942, the cross-linking theory of aging postulates that aging results from the accumulation of intra-intermolecular covalent bonds (crosslinks) between molecules with slow turnovers, such as collagen and elastin of the extracellular matrix (ECM). These crosslinks affect the physical properties of the ECM (i. e. stiffness) which may cause cell dysfunction via mechanosensing. Additionally, there also exist adducts which may cause inflammation via activation of the receptor for advanced glycation endproducts (RAGE). We also think that ECM aging might be even more important than cellular aging since cells have effective mechanisms to repair or remove damaged proteins and organelles.

These modifications are a consequence of the biochemistry and the long turnover of some macromolecules and do not require any dysregulation of molecular pathways. Additionally, these modifications give rise to virtually all hallmarks of aging and age-related pathologies, which makes it an ideal candidate for the starting point of the vicious cycle of aging. Organisms with remarkably long lifespans like bowhead whale have exceptionally low rates of advanced glycation endproducts accumulation, which gives a hope that interventions that slow down the accumulation of non-enzymatic modifications should dramatically decrease the rate of aging and thus prolong both lifespan and healthspan.