On the enigma of carnosine’s anti-ageing actions

Abstract

Carnosine ( -alanyl-L-histidine) has described as a forgotten and enigmatic dipeptide. Carnosine's enigma is particularly exemplified by its apparent anti-ageing actions; it suppresses cultured human fibroblast senescence and delays ageing in senescence-accelerated mice and Drosophila, but the mechanisms reponsible remain uncertain. In addition to carnosine's well-documented anti-oxidant, anti-glycating, aldehyde-scavenging and toxic metal-ion chelating properties, its ability to influence the metabolism of altered polypeptides, whose accumulation characterises the senescent phenotype, should also be considered. When added to cultured cells, carnosine was found in a recent study to suppress phosphorylation of the translational initiation factor eIF4E resulting in decreased translation frequency of certain mRNA species. Mutations in the gene coding for eIF4E in nemtodes extend organism lifespan, hence carnosine's anti-ageing effects may be a consequence of decreased error-protein synthesis which in turn lowers formation of protein carbonyls and increases protease availability for degradation of polypeptides altered postsynthetically. Other studies have revealed carnosine-induced upregulation of stress protein expression and nitric oxide synthesis, both of which may stimulate proteasomal elimination of altered proteins. Some anti-convulsants can enhance nematode longevity and suppress the effects of a protein repair defect in mice, and as carnosine exerts anti-convulsant effects in rodents, it is speculated that the dipeptide may participate in the repair of protein isoaspartyl groups. These new observations only add to the enigma of carnosine's real in vivo functions. More experimentation is clearly required. ACCEPTED MANUSCRIPT 3 Carnosine and ageing.The naturally-occurring dipeptide carnosine ( -alanyl-L-histidine) has been described as forgotten and enigmatic (Bauer, 2005): the present paper is an attempt to rectify the former opinion, but, however only adds to the latter view. Amongst carnosine's enigmatic properties are its apparent anti-ageing actions; the dipeptide is one of a very few naturally-occurring compounds which suppresses cell senescence, induces rejuvenating effects Holliday, 1994 and, and protects against telomere shortening (Shao et al., 2004) in cultured human fibroblasts. The dipeptide also extends the life-span of senescence-accelerated mice (Yuneva et al., 1999) and Drosophila (Yuneva et al., 2002). There are many possible mechanisms by which carnosine exerts these anti-ageing actions however, some of which were summarized a decade ago (Hipkiss, 1998). Meanwhile there have been a number of publications suggesting further possible routes by which carnosine could suppress

Carnosine and cancer: a perspective

“…This conclusion is exemplified by carnosine's contrasting effects on tumour cells and differentiated fibroblasts (Hipkiss 2009a), whilst carnosine extends the proliferative potential of cultured human fibroblasts, lengthens their lifespan and suppresses the appearance of the senescent phenotype (McFarland and Holliday 1994), the dipeptide strongly inhibits the growth of cultured tumour cells, as outlined above. It is possible, however, to reconcile this apparent paradox when one considers the metabolic differences between these two cell types, i.e.…”

“…A further interesting observation that may hint at a possible mechanism is the finding that some advanced glycation end products (AGEs) inhibit tumour growth (Bartling et al 2011). In fact, carnosine's ability to react with AGEs and many AGEinducing agents is one of its likely biological functions [for a recent review see (Hipkiss 2009a)]. Another aspect may be hidden behind carnosine's ability to scavenge reactive oxygen species (ROS) (Gorbunov and Erin 1991) [for review see (Guiotto et al 2005;Boldyrev et al 2007;Boldyrev 1993)].…”

Role of Glutamate Decarboxylase-like Protein 1 (GADL1) in Taurine Biosynthesis

“…In addition to muscles, carnosine is also found in brains and hearts and is therefore suspected to be more than a buffering reagent in physiology (26 -30). Studies of carnosine have suggested that it has neuroprotective (31, 32), antiglycative (33), antioxidative (34), and anti-aging activities (35,36).…”

Molecular Identification of Carnosine Synthase as ATP-grasp Domain-containing Protein 1 (ATPGD1)

“…It has also been proposed to be an anti-glycation agent (for review, see Ref. 6) and a blood glucose regulator (7), whereas the dipeptide present in the olfactory system might be either a neurotransmitter or a neuromodulator (for review, see Ref. 8).…”