Life Sciences Research for Lifelong Health

Michael Wakelam

Research Summary

We aim to understand the essential physiological functions of lipids. Lipids are highly dynamic structures with structural, metabolic and signalling roles. To fully understand the roles that lipids have in cell function during ageing we need the ability to determine their individual changes.

The cellular lipidome is extremely complex, with distinct classes of lipids each containing many molecular species that can differ both in the length of each acyl chain present and in the number and position of double bonds.

In our lab we have pioneered the use of high-sensitivity liquid chromatography-mass spectrometry (LC-MS) technology to rapidly and comprehensively measure the levels of lipids in a wide range of cell types, tissues and tumours. The lipidome of a cell typically comprises of ~ 1500 distinct lipid species measurable with current LC-MS technology. However, this number is most likely an underestimate since there are theoretically closer to 10 000 distinct lipid species in the lipidome.

The principal aim of our laboratory is to better understand how the distinct lipid species of a cell’s lipidome function during the healthy ageing of the whole animal.

​To achieve this we use a multidisciplinary approach combining LC-MS analysis, protein biochemistry, cell biology and genetic manipulation of model organisms. This allows us to identify the cellular signalling pathways and processes that individual lipid species regulate, and to investigate how the enzymes that determine the composition of the lipidome are regulated in response to changes in the environment.

Latest Publications

A nutritional memory effect counteracts benefits of dietary restriction in old mice.
Hahn O, Drews LF, Nguyen A, Tatsuta T, Gkioni L, Hendrich O, Zhang Q, Langer T, Pletcher S, Wakelam MJO, Beyer A, Grönke S, Partridge L

Dietary restriction (DR) during adulthood can greatly extend lifespan and improve metabolic health in diverse species. However, whether DR in mammals is still effective when applied for the first time at old age remains elusive. Here, we report results of a late-life DR switch experiment employing 800 mice, in which 24 months old female mice were switched from ad libitum (AL) to DR or vice versa. Strikingly, the switch from DR-to-AL acutely increases mortality, whereas the switch from AL-to-DR causes only a weak and gradual increase in survival, suggesting a memory of earlier nutrition. RNA-seq profiling in liver, brown (BAT) and white adipose tissue (WAT) demonstrate a largely refractory transcriptional and metabolic response to DR after AL feeding in fat tissue, particularly in WAT, and a proinflammatory signature in aged preadipocytes, which is prevented by chronic DR feeding. Our results provide evidence for a nutritional memory as a limiting factor for DR-induced longevity and metabolic remodeling of WAT in mammals.

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Nature metabolism, 1, 2522-5812, 1059-1073, 2019

PMID: 31742247

Lipidomics: Current state of the art in a fast moving field.
O'Donnell VB, Ekroos K, Liebisch G, Wakelam M

Lipids are essential for all facets of life. They play three major roles: energy metabolism, structural, and signaling. They are dynamic molecules strongly influenced by endogenous and exogenous factors including genetics, diet, age, lifestyle, drugs, disease and inflammation. As precision medicine starts to become mainstream, there is a huge burgeoning interest in lipids and their potential to act as unique biomarkers or prognostic indicators. Lipids comprise a large component of all metabolites (around one-third), and our expanding knowledge about their dynamic behavior is fueling the hope that mapping their regulatory biochemical pathways on a systems level will revolutionize our ability to prevent, diagnose, and stratify major human diseases. Up to now, clinical lipid measurements have consisted primarily of total cholesterol or triglycerides, as a measure for cardiovascular risk and response to lipid lowering drugs. Nowadays, we are able to measure thousands of individual lipids that make up the lipidome. nuclear magnetic resonance spectrometry (NMR) metabolomics is also being increasingly used in large cohort studies where it can report on total levels of selected lipid classes, and relative levels of fatty acid saturation. To support the application of lipidomics research, LIPID MAPS was established in 2003, and since then has gone on to become the go-to resource for several lipid databases, lipid drawing tools, data deposition, and more recently lipidomics informatics tools, and a lipid biochemistry encyclopedia, LipidWeb. Alongside this, the recently established Lipidomics Standards Initiative plays a key role in standardization of lipidomics methodologies. This article is categorized under: Laboratory Methods and Technologies > Metabolomics Analytical and Computational Methods > Analytical Methods.

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Wiley interdisciplinary reviews. Systems biology and medicine, , 1939-005X, e1466, 2019

PMID: 31646749

The circadian clock components BMAL1 and REV-ERBα regulate flavivirus replication.
Zhuang X, Magri A, Hill M, Lai AG, Kumar A, Rambhatla SB, Donald CL, Lopez-Clavijo AF, Rudge S, Pinnick K, Chang WH, Wing PAC, Brown R, Qin X, Simmonds P, Baumert TF, Ray D, Loudon A, Balfe P, Wakelam M, Butterworth S, Kohl A, Jopling CL, Zitzmann N, McKeating JA

The circadian clock regulates immune responses to microbes and affects pathogen replication, but the underlying molecular mechanisms are not well understood. Here we demonstrate that the circadian components BMAL1 and REV-ERBα influence several steps in the hepatitis C virus (HCV) life cycle, including particle entry into hepatocytes and RNA genome replication. Genetic knock out of Bmal1 and over-expression or activation of REV-ERB with synthetic agonists inhibits the replication of HCV and the related flaviruses dengue and Zika via perturbation of lipid signaling pathways. This study highlights a role for the circadian clock component REV-ERBα in regulating flavivirus replication.

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Nature communications, 10, 2041-1723, 377, 2019

PMID: 30670689

Group Members

Latest Publications

A nutritional memory effect counteracts benefits of dietary restriction in old mice.

Hahn O, Drews LF, Nguyen A

Nature metabolism
1 2522-5812:1059-1073 (2019)

PMID: 31742247

Lipidomics: Current state of the art in a fast moving field.

O'Donnell VB, Ekroos K, Liebisch G

Wiley interdisciplinary reviews. Systems biology and medicine
1939-005X:e1466 (2019)

PMID: 31646749

The circadian clock components BMAL1 and REV-ERBα regulate flavivirus replication.

Zhuang X, Magri A, Hill M

Nature communications
10 2041-1723:377 (2019)

PMID: 30670689

LIPID MAPS: Serving the next generation of lipid researchers with tools, resources, data, and training.

O'Donnell VB, Dennis EA, Wakelam MJO

Science signaling
12 1937-9145: (2019)

PMID: 30622195

Modeling Meets Metabolomics-The WormJam Consensus Model as Basis for Metabolic Studies in the Model Organism .

Witting M, Hastings J, Rodriguez N

Frontiers in molecular biosciences
5 2296-889X:96 (2018)

PMID: 30488036

3D growth of cancer cells elicits sensitivity to kinase inhibitors but not lipid metabolism modifiers.

Jones DT, Valli A, Haider S

Molecular cancer therapeutics
1538-8514: (2018)

PMID: 30478149

CD151 regulates expression of FGFR2 in breast cancer cells via PKC-dependent pathways.

Sadej R, Lu X, Turczyk L

Journal of cell science
1477-9137: (2018)

PMID: 30257985

C. elegans Eats Its Own Intestine to Make Yolk Leading to Multiple Senescent Pathologies.

Ezcurra M, Benedetto A, Sornda T

Current biology : CB
1879-0445: (2018)

PMID: 30100339

Extracellular vesicles : lipids as key components of their biogenesis and functions.

Record M, Silvente-Poirot S, Poirot M

Journal of lipid research
1539-7262: (2018)

PMID: 29764923