Late Life Asparagine Endopeptidase Inhibition Extends Lifespan in Mice
Few interventions have been demonstrated to slow aging or address age-related damage to a sufficient degree to extend mouse life span by 15% or more if applied starting at a late age. The requirement to start late in life cuts down the field of possibilities quite dramatically. Today's open access paper stakes a claim for inhibition of asparagine endopeptidase activity to be included in the small number of interventions capable of this sort of outcome. The researchers started treating mice at 18 months of age, roughly equivalent to 50-something in humans, and saw a four month gain in median survival, from 24 to 28 months. For comparison, this is in the same ballpark as the results of rapamycin treatment started in late life in mice.
Rapamycin is a calorie restriction mimetic, with benefits to cell function, tissue function, health and aging emerging through increased efficiency in the operation of the cellular maintenance processes of autophagy. This improves mitochondrial function by better clearing dysfunction mitochondria, helps cells resist entering a senescent state and thus reduces the burden of senescence in aged tissues, and helps ameliorate a range of other noted contributions to the aging process. Inhibition of asparagine endopeptidase activity arrives at a similar outcome via a different path; again better mitochondrial function and a reduced burden of senescence, though here this is argued to arise from a direct improvement of mitochondrial metabolism that may or may not involve improved autophagy.
Inhibition of asparagine endopeptidase extends the lifespan and improves health span during aging
Asparagine endopeptidase (AEP), alternatively referred to as legumain (LGMN), is a cysteine protease activated under acidic conditions and belongs to the C13 peptidase family. As an enzyme, AEP specifically cleaves its substrates after asparagine residues and is primarily localized to the endo-lysosomal system; however, under pathophysiological conditions, AEP is also localized in the cytoplasm or in the nucleus. Increasing evidence links aberrant AEP activation to multiple age-associated pathological processes, particularly in tissues exposed to lysosomal stress and chronic inflammation. In this state, AEP cleaves a range of target proteins, generating fragmented, often pathogenic, versions that contribute to cellular dysfunction. Aging is also associated with a decline in autophagy, the cell's recycling process. Dysregulated AEP activity may contribute to this decline by perturbing lysosomal function and proteolytic homeostasis, leading to the accumulation of damaged proteins and organelles.
Our findings support the idea that AEP is involved in multiple aging-associated pathological processes and that pharmacological inhibition of AEP may ameliorate several age-related phenotypes. In the current work, AEP inhibitor #11a alleviated multiple frailty indices in both male and female mice and was associated with attenuated age-related decline in physical and cognitive functions. In parallel, #11a reduced NAMPT cleavage and was associated with higher NAD-related readouts together with elevated SIRT1 and PGC-1α levels. #11a treatment was also associated with improved insulin sensitivity and reduced adiposity-related changes in brown adipose tissue and inguinal white adipose tissue. Furthermore, #11a reduced senescence-associated β-galactosidase staining and lowered several senescence- and inflammation-associated markers in multiple organs. Together, these observations are consistent with our recent report that administration of nicotinamide mononucleotide (NMN) or #11a ameliorates age-related disorders and extends lifespan in Thy1-C/EBPβ transgenic mice and worms, further supporting AEP as a therapeutically relevant target.
Our data support a model in which inhibition of AEP via #11a suppresses NAMPT cleavage and is associated with improved NAD-related readouts, thereby potentially contributing to reduced senescence-associated changes. Although these findings are consistent with a model in which #11a modulates the AEP-NAMPT-NAD+/SIRT1/PGC-1α pathway, the current evidence remains largely correlative in naturally aged mice. Additional causal studies will be needed to determine the extent to which this pathway is required for the survival and health span phenotypes observed here.