Novel targets for delaying aging: The importance of the liver and advances in drug delivery

Abstract

Age-re lated changes in liver func tion have a sig nif i cant im pact on sys temic ag ing and sus cep ti bil ity to agere lated dis eases. Nu tri ent sens ing path ways have emerged as im por tant tar gets for the de vel op ment of drugs that de lay ag ing and the on set age-re lated dis eases. This sup ports a cen tral role for the he patic reg ula tion of me tab o lism in the as so ci a tion be tween nu tri tion and ag ing. Re cently, a role for liver si nu soidal en dothe lial cells (LSECs) in the re la tion ship be tween ag ing and me tab o lism has also been pro posed. Agere lated loss of fen es tra tions within LSECs im pairs the trans fer of sub strates (such as lipopro teins and insulin) be tween si nu soidal blood and he pa to cytes, re sult ing in post-pran dial hy per lipi demia and in sulin resis tance. Tar geted drug de liv ery meth ods such as nanopar ti cles and quan tum dots will fa cil i tate the di rect de liv ery of drugs that reg u late fen es tra tions in LSECs, pro vid ing an in no v a tive ap proach to ame lio rat ing age-re lated dis eases and in creas ing healthspan.

The Endothelium as a Driver of Liver Fibrosis and Regeneration

“…Serum albumin targets almost entirely stabilin-2 receptors [265]. This ligand has been used to increase LSEC delivery by coating liposomes [266], lipid particles [267] and quantum dots [268].…”

“…Besides that, adenovirus with the endothelial cell specific ROBO4 promoter have been seen to present a high degree of LSEC specificity and have been used to promote liver regeneration while bypassing fibrosis [218]. Finally, quantum dots (QDs), a type of nanoparticles with a size between 1-20 nm that present quantum effects [265] are also an area or interest [265]. Telluride/cadmium sulphide QDs [273] and Zn-labelled CdSelenide/CdS/ZnS QDs have been shown to effectively ameliorate LSEC delivery [274].…”

“…Besides nanoparticle coating, particle size has to be taken into account since nanoparticles bigger than 250 nm are directly taken up by KC for being too big to pass through fenestrae. Contrarily, those with a diameter between 5-20nm particularly target LSEC [265,275].…”

LSEC model of aging

“…Age-induced pseudocapillarization is a sequential process, starting with defenestration at a relatively young age and progressing towards LSEC thickening and fibrosis later in life ( Figure 1) [30]. In turn, finding approaches to reverse defenestration and pseudocapillarization have being actively and successfully pursued in several laboratories as a strategy to ameliorate some age-related diseases [52][53][54][55].…”

The effect of aerobic training with Citrus aurantium L. on SIRT1 and PGC-1α gene expression levels in the liver tissue of elderly rats

“…FOXO is regulated by NAD + /SIRT1, insulin-like growth factor 1, AMPK, and oxidative stress, all of which are affected by aging. SIRT1 is involved in the regulation of several key proteins related to aging, glucose homeostasis, lipid metabolism, autophagy, inflammation, apoptosis, and cellular changes (6,7). SIRT1 activity is dependent on NAD + and has been shown to play a role in the beneficial effects of CR on longevity (8).…”