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Biomedical subjects

Alan R Hipkiss

Publications and source records attributed to Alan R Hipkiss.

14 recordsLinked to original sources
PubMed2006

Dietary restriction, glycolysis, hormesis and ageing.

The possibility is discussed that dietary restriction modulates ageing and onset of related pathologies by, in addition to upregulation of proteolysis, suppression of glycolysis which in turn decreases generation of methylglyoxal (MG), a highly toxic glycating agent which can provoke cellular senescence and many age-related pathologies. This proposal is supported by the observation that intermittent feeding can mimic dietary restriction's effects on mouse lifespan without any overall reduction in calorie intake. That MG-induced modification of the chaperone and anti-apoptotic protein (Hsp27) increases its protective functions suggests a possible hormetic response to transient MG production during transient periods of glycolysis in dietary restricted animals. It is suggested that in the ad libitum-fed state permanent glycolysis would suppress proteolysis and continuously generate MG which overwhelms the anti-MG defence systems. It is proposed that periods of fasting might be a more acceptable approach than permanent undernutrition in our attempts to slow human ageing, although timing of meals may prove important.

Aging↗
PubMed2006

Accumulation of altered proteins and ageing: causes and effects.

Accumulation of altered proteins is the most common molecular symptom of ageing. Altered proteins are also associated with many age-related pathologies. Altered proteins are continuously produced but are normally selectively degraded by cellular proteases; their accumulation during ageing may be explained by either or both increased production or decreased elimination. Sources of altered proteins include erroneous synthesis by cytoplasmic and mitochondrial ribosomes, spontaneous deamidation, isomerization and racemization of unstable amino acids residues, damage inflicted by reactive oxygen and nitrogen species, and glycation and cross-linking by glucose and more reactive metabolites. Glycated proteins may damage mitochondria to increase production of reactive oxygen species, while highly oxidised/cross-linked polypeptides may resist proteolysis, inhibit proteasome function and induce a permanent stress response. Other possible explanations for the age-related changes in the defence systems, enzymatic and non-enzymatic, which normally counter generation of altered proteins are also discussed.

Aging↗
PubMed2006

Does chronic glycolysis accelerate aging? Could this explain how dietary restriction works?

The mechanisms by which dietary restriction (DR) suppresses aging are not understood. Suppression of glycolysis by DR could contribute to controlling senescence. Many glycolytic intermediates can glycate proteins and other macromolecules. Methyglyoxal (MG), formed from dihydroxyacetone- and glyceraldehyde-3-phosphates, rapidly glycates proteins, damages mitochondria, and induces a prooxidant state to create a senescent-like condition. Ad libitum-fed and DR animals differ in mitochondrial activity and glycolytic flux rates. Persistent glycolysis in the unrestricted condition would increase the intracellular load of glycating agents (e.g., MG) and increase ROS generation by inactive mitochondria. Occasional glycolysis during DR would decrease MG and reactive oxygen species (ROS) production and could be hormetic, inducing synthesis of glyoxalase-1 and anti-glycating agents (carnosine and polyamines).

Aging↗
PubMed2006

Would carnosine or a carnivorous diet help suppress aging and associated pathologies?

Carnosine (beta-alanyl-L-histidine) is found exclusively in animal tissues. Carnosine has the potential to suppress many of the biochemical changes (e.g., protein oxidation, glycation, AGE formation, and cross-linking) that accompany aging and associated pathologies. Glycation, generation of advanced glycosylation end-products (AGEs), and formation of protein carbonyl groups play important roles in aging, diabetes, its secondary complications, and neurodegenerative conditions. Due to carnosine's antiglycating activity, reactivity toward deleterious carbonyls, zinc- and copper-chelating activity and low toxicity, carnosine and related structures could be effective against age-related protein carbonyl stress. It is suggested that carnivorous diets could be beneficial because of their carnosine content, as the dipeptide has been shown to suppress some diabetic complications in mice. It is also suggested that carnosine's therapeutic potential should be explored with respect to neurodegeneration. Olfactory tissue is normally enriched in carnosine, but olfactory dysfunction is frequently associated with neurodegeneration. Olfactory administration of carnosine could provide a direct route to compromised tissue, avoiding serum carnosinases.

Aging↗
PubMed2005

On the mechanisms of ageing suppression by dietary restriction-is persistent glycolysis the problem?

The mechanism(s) by which dietary restriction (DR) suppresses ageing and onset of age-related pathologies are discussed in relation to frequency of glycolysis, and the reactivity of glycolytic intermediates. Most glycolytic intermediates are potentially toxic and readily modify (i.e. glycate) proteins and other macromolecules non-enzymically. Attention is drawn to the reactivity of methyglyoxal (MG) which is formed predominantly from the glycolytic intermediates dihydroxyacetone- and glyceraldehyde-3-phosphates. MG rapidly glycates proteins, damages mitochondria and induces a pro-oxidant state, similar to that observed in aged cells. It is suggested that because DR animals' energy metabolism is less glycolytic than in those fed ad libitum, intracellular MG levels are lowered by DR The decreased glycolysis during DR may delay senescence by lowering intracellular MG concentration compared to ad libitum-fed animals. Because of the reactivity MG and glycolytic intermediates, occasional glycolysis could be hormetic where glyoxalase, carnosine synthetase and ornithine decarboxylase are upregulated to control cellular MG concentration. It is suggested that in ad libitum-fed animals persistent glycolysis permanently raises MG levels which progressively overwhelm protective processes, particularly in non-mitotic tissues, to create the senescent state earlier than in DR animals. The possible impact of diet and intracellular glycating agents on age-related mitochondrial dysfunction is also discussed.

Aging↗
PubMed2005

Could carnosine suppress zinc-mediated proteasome inhibition and neurodegeneration? Therapeutic potential of a non-toxic but non-patentable dipeptide.

Ageing and neurodegenerative conditions are often associated with proteasome dysfunction, possibly mediated by zinc and/or copper ions. Studies have shown that (i) the olfactory lobe is normally enriched in carnosine and zinc, (ii) carnosine can suppress copper and zinc toxicity in olfactory neurones, (iii) olfactory dysfunction is often associated with neurodegenerative conditions and (iv) elevated levels of zinc are found in brains of Alzheimer's patients. It is suggested that nasal administration of carnosine should be explored as a possible way of suppressing zinc/copper-mediated proteasome inhibition and consequent neurodegeneration.

Animals↗
PubMed2005

Glycation, ageing and carnosine: are carnivorous diets beneficial?

Non-enzymic protein glycosylation (glycation) plays important roles in ageing and in diabetes and its secondary complications. Dietary constituents may play important roles in accelerating or suppressing glycation. It is suggested that carnivorous diets contain a potential anti-glycating agent, carnosine (beta-alanyl-histidine), whilst vegetarians may lack intake of the dipeptide. The possible beneficial effects of carnosine and related structures on protein carbonyl stress, AGE formation, secondary diabetic complications and age-related neuropathology are discussed.

Aging↗
PubMed2004

Is carnosine a naturally occurring suppressor of oxidative damage in olfactory neurones?

Ghanbari et al. recently showed that neurones from olfactory lobes of Alzheimer's patients exhibit oxidative stress and it is well known that olfactory dysfunction frequently accompanies neurodegeneration. The olfactory lobe is normally enriched in carnosine, a relatively non-toxic (and sometimes abundant) dipeptide which possesses functions (anti-oxidant, antiglycator, scavenger of zinc and copper ions, toxic aldehydes and protein carbonyls) that are likely to suppress oxidative stress. It is suggested that carnosine's therapeutic potential should be explored in olfactory tissue. Should the peptide prove beneficial, olfactory carnosine administration could provide a direct route to compromised tissue, avoiding serum carnosinases.

Animals↗
PubMed2003

Do developmentally-related changes in constitutive proteolysis affect aberrant protein accumulation and generation of the aged phenotype?

This article considers whether developmentally-related changes in protein synthesis regulate constitutive cellular ability to degrade aberrant polypeptides and thereby contribute to the generation of the aged phenotype. It is suggested that low levels in constitutive ability to deal with aberrant proteins lower the threshold for induction of the stress response and increase cellular vulnerability to insults which characterizes the senescent state. It is proposed that developmentally-regulated diminution of constitutive proteolytic activities contribute to the onset of age-relate pathologies.

Aging↗
PubMed2003

Errors, mitochondrial dysfunction and ageing.

Experiments in yeast have shown that increasing the accuracy of mitochondrial ribosomes increases cellular lifespan, which suggests that mitochondrial ribosomal inaccuracy could be a potential source age-related mitochondrial dysfunction. It is argued that experiments used to test the error-catastrophe theory of ageing could therefore be invalid because only proteins synthesized on 80S cytoplasmic ribosomes were analyzed. It is speculated that in elderly mammals, when growth and mitochondrial replacement rates decline, the increased organelle dwell-time allows manifestation of any loss of mito-ribosomal accuracy. The resultant aberrant polypeptides could then overload the Lon protease, which also degrades oxidatively damaged polypeptides, and thereby contribute to the accumulation of damaged macromolecules, mitochondrial dysfunction and senescence. It is suggested that a search for age-related changes in the accuracy of mitochondrial ribosomes be carried out to test the validity or otherwise of these ideas.

ATP-Dependent Proteases↗
PubMed2002

Reaction of carnosine with aged proteins: another protective process?

Cellular aging is often associated with an increase in protein carbonyl groups arising from oxidation- and glycation-related phenomena and suppressed proteasome activity. These "aged" polypeptides may either be degraded by 20S proteasomes or cross-link to form structures intractable to proteolysis and inhibitory to proteasome activity. Carnosine (beta-alanyl-l-histidine) is present at surprisingly high levels (up to 20 mM) in muscle and nervous tissues in many animals, especially long-lived species. Carnosine can delay senescence in cultured human fibroblasts and reverse the senescent phenotype, restoring a more juvenile appearance. As better antioxidants/free-radical scavengers than carnosine do not demonstrate these antisenescent effects, additional properties of carnosine must contribute to its antisenescent activity. Having shown that carnosine can react with protein carbonyls, thereby generating "carnosinylated" polypeptides using model systems, we propose that similar adducts are generated in senescent cells exposed to carnosine. Polypeptide-carnosine adducts have been recently detected in beef products that are relatively rich in carnosine, and carnosine's reaction with carbonyl functions generated during amino acid deamidation has also been described. Growth of cultured human fibroblasts with carnosine stimulated proteolysis of long-labeled proteins as the cells approached their "Hayflick limit," consistent with the idea that carnosine ameliorates the senescence-associated proteolytic decline. We also find that carnosine suppresses induction of heme-oxygenase-1 activity following exposure of human endothelial cells to a glycated protein. The antisenescent activity of the spin-trap agent alpha-phenyl-N-t-butylnitrone (PBN) towards cultured human fibroblasts resides in N-t-butyl-hydroxylamine, its hydrolysis product. As hydroxylamines are reactive towards aldehydes and ketones, the antisenescent activity of N-t-butyl-hydroxylamine and other hydroxylamines may be mediated, at least in part, by reactivity towards macromolecular carbonyls, analogous to that proposed for carnosine.

Amino Acids↗