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  • Review Article
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Ageing and metabolism: drug discovery opportunities

Key Points

  • Ageing is a major risk factor for several major diseases, including cancers, cardiovascular, metabolic and neurodegenerative diseases.

  • The molecular mechanisms governing the ageing process have been elucidated during the past decade and suggest that manipulations of specific pathways and genes can increase healthy lifespan.

  • Many of the genes that affect lifespan belong to evolutionarily conserved pathways known to be intricately involved in the control of energy metabolism. In addition, several of these genes represent good molecular targets for drug discovery for the major metabolic diseases (such as obesity and type 2 diabetes).

  • Phenotypic and molecular links between ageing and metabolism reveal that insulin resistance and visceral fat accumulation are culprits in the pathogenesis of metabolic disease and predispose organisms to premature ageing.

  • Approaches for drug discovery in this arena include reducing calorie intake, regulating the function of adipocytes, modulating AMP-activated kinase, lowering insulin/insulin-like growth factor 1 signalling in select tissues (for example, fat) and modulating mammalian Sir2 homologues (SIRT) deacetylase activities.

  • Targeting the mechanisms of ageing provides a novel means of discovering drugs for metabolic diseases as well as other important age-related diseases. In addition, drugs currently used to treat metabolic disorders (for example, metformin) could extend lifespan and have utility in treating other age-related diseases.

Abstract

There has recently been significant progress in our understanding of the mechanisms that regulate ageing, and it has been shown that changes in single genes can dramatically extend lifespan and increase resistance to many diseases. Furthermore, many of these genes belong to evolutionarily conserved pathways that also control energy metabolism. In this review, we describe the shared molecular machinery that regulates ageing and energy metabolism. Although drugs to slow ageing face severe regulatory hurdles, it is likely that an understanding of ageing pathways will help to identify novel drug targets to treat metabolic disorders and other age-related diseases.

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Figure 1: Ageing is a risk factor for a large number of impairments and diseases.
Figure 2: Conserved regulation of lifespan in Caenorhabditis elegans and mice by the insulin/IGF-1 pathway.
Figure 3: Tissue cross-talk in the regulation of blood-glucose levels.
Figure 4: Potential pharmacological entry points into the AMPK pathway.
Figure 5: Potential therapeutic entry points into the GH–IGF-1 axis.

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Acknowledgements

We wish to thank J. Apfeld for invaluable insights and intellectual input. We also thank C. Bayley and J. Solomon for helpful discussions and comments on the manuscript.

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Correspondence to Peter S. DiStefano.

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Competing interests

The authors are employees of Elixir Pharmaceuticals, which is developing drugs based on the research described in this article.

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DATABASES

Entrez Gene

ACC-2

adiponectin

adipsin

AMPK

daf-2

grehlin receptor

IGF-1

insulin

leptin

melanocortin 4 receptor

PPARδ

resistin

Sir2

SIRT1

SIRT3

OMIM

Alzheimer's disease

Parkinson's disease

Glossary

TYPE 2 DIABETES

Also referred to as adult-onset or non-insulin-dependent diabetes, type 2 diabetes is primarily a disease of insulin insensitivity and is characterized by elevated insulin levels, early in the disease.

ENERGY HOMEOSTASIS

The tendency to maintain the stability of normal biological states during adjustments to environmental changes.

CALORIE RESTRICTION

Limiting of macronutrient sources of protein, carbohydrate and lipid while maintaining micronutrient sources.

METFORMIN

A member of the biguanide drug class, related to guanidine and the standard of care for type 2 diabetes. The related drugs phenformin and buformin have been withdrawn from the market.

VISCERAL FAT MASS

White fat tissue associated with the body cavities (particularly with organs in the abdominal cavity) that is anatomically and physiologically distinct from subcutaneous fat.

INSULIN SENSITIVITY

The capacity of cells to respond to insulin-stimulated glucose uptake following ingestion of carbohydrates.

ADIPOGENESIS

The development of fat precursor cells into mature white or brown fat tissue.

ADIPOKINES

Proteinaceous factors produced or released by fat cells.

HYPERINSULINAEMIA

Blood insulin levels that exceed normal physiological fluctuations of fasting and feeding.

METABOLIC SYNDROME

A constellation of dysfunctions in glucose metabolism (such as insulin sensitivity and glucose tolerance), lipid metabolism and cardiac function; also referred to as syndrome X or insulin-resistance syndrome.

HYPOTHALAMUS

A region of the diencephalon lying below the thalamus that controls feeding, thirst, body temperature, sleep and emotion, as well as pituitary and autonomic functions.

FATTY-ACID OXIDATION

The burning of stored fat or fats obtained through the diet. Also known as β-oxidation, it efficiently produces NADH, FADH2 and acetyl co-enzyme A.

ACROMEGALY

Enlargement of the hands, feet, head and face due to overproduction of growth hormone by the anterior pituitary gland.

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Curtis, R., Geesaman, B. & DiStefano, P. Ageing and metabolism: drug discovery opportunities. Nat Rev Drug Discov 4, 569–580 (2005). https://doi.org/10.1038/nrd1777

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