Filipe Cabreiro

FMNS | Institute for Genetics (UoC) & Microbiota in Aging (CECAD)

Prof. Dr. Filipe Gomes Cabreiro

Principal Investigator
Head of Research Area 3

+49 221 478 84390

f.cabreiro[at]uni-koeln.de

Website

cabreirolab

Research Areas

Microbiota in aging

Aging arises from the complex interaction between the host genetics and its environment. The microbiota regulates the propensity for ill-health throughout aging but the dynamics and factors that govern these interactions are poorly understood.

Research Focus

We aim at developing experimental and computational tools to study the causal relationship between host genetics, microbial genetics and nutrient interactions in the context of aging. Our objective is discovering pharmacological and/or pharmacomicrobiomic (drug-microbe) approaches to treat metabolic disease and improve aging.

Our Goals

Our work has been focusing on understanding in great detail the mechanistic role played by microbes and/or nutrition in aging and healthspan.

My team and I have recently investigated the effect of genetic, dietary, and microbial impact on worm healthspan and lifespan. In particular, we found that worms that are grown with a vitamin B12 high-producing bacterial strain compared to a low-producing one such as E. coli, maintain their healthspan for longer during aging (Essmann et al., 2020, Nature Comms).
We have also developed a high-throughput screening approach to study the interaction between host genetics and environmental stresses or pathogenic infection (Benedetto et al., 2019, Aging Cell). These studies further support a key role for microbial commensalism and pathogenicity in regulating healthspan and lifespan in a host genetic-dependent manner. Importantly, we have developed novel 3 and 4-way high-throughput drug-microbe-host screens that allowed us to define the key signaling and metabolic pathways in bacteria that regulate the host response to therapeutic drugs. In a 3-way high-throughput drug screen of drug-microbe and C. elegans using the Keio collection of E. coli single gene deletion mutants (Scott et al., 2017, Cell), we tested more than 55,000 individual conditions, and identified vitamins B6 and B9 and ribonucleotide metabolism as key microbial contributors to 5-FU action, an anti-cancer drug. This work also implicates a role of microbes in controlling autophagy, one of the key mechanisms regulating aging (Lopez-Otin et al., 2013).

Further, we have investigated the role of the dietary-restriction mimetic metformin, the most widely prescribed type 2 diabetes drug, in regulating aging. We and others have shown that metformin regulates host physiology and aging by altering the microbiota (Pryor et al., 2019, Cell; Cabreiro et al., 2013, Cell). Our work shows that the effects of metformin on host lipid metabolism and lifespan, depend on both E. coli and nutrition, providing a mechanistic explanation for human data. This was made possible using a combination of C. elegans, Drosophila and human microbiome computational modeling together with and an array of multi-omic, screening, biochemical and genetic approaches at the host and microbial level. Overall, our 4-way drug-microbe-nutrient-host high-throughput screening approach led to the identification of a nutrient signaling pathway in bacteria that, when activated by metformin, regulates the positive effects of the drug on the host lipid metabolism. We have recently used the worm as a model to validate a novel mode of action employed by bacteria to reduce drug efficacy on the host (Klunneman et al., 2021, Nature).
Finally, using C. elegans and a synthetic biology approach, we characterized whole-cell bacterial biosensors in vivo in an aging host. We were able to show that these bacterial sensors are capable of detecting and reporting on changes inside the intestine of C. elegans after introducing exogenous chemical inducers into the environment (Rutter et al., 2019). This work provides evidence that C. elegans is colonized by microbes that are alive and functionally respond to cues within their intestinal environment throughout aging.
Our work on the effects of drugs and longevity has also revealed that rapamycin extends longevity through a novel aging mechanism – improved protein fidelity, in an evolutionarily conserved manner (Martinez et al., 2021, Cell Metabolism).

Key Publications

Martinez-Miguel, V.E., Lujan, C., Espie-Caullet, T., Martinez-Martinez, D., Moore, S., Backes, C., Gonzalez, S., Galimov, E.R., Brown, A.E.X., Halic, M., Tomita, K., Rallis, C., von der Haar, T., Cabreiro, F.^#, and Bjedov, I.^# (2021). Increased fidelity of protein synthesis extends lifespan. Cell Metab 33, 2288-2300 e2212. 10.1016/j.cmet.2021.08.017. (# Co-corresponding last authors)
Essmann, C.L., Martinez-Martinez, D., Pryor, R., Leung, K.Y., Krishnan, K.B., Lui, P.P., Greene, N.D.E., Brown, A.E.X., Pawar, V.M., Srinivasan, M.A., and Cabreiro, F. (2020). Mechanical properties measured by atomic force microscopy define health biomarkers in ageing C. elegans. Nat Commun 11, 1043. 10.1038/s41467-020-14785-0.
Pryor, R., Norvaisas, P., Marinos, G., Best, L., Thingholm, L.B., Quintaneiro, L.M., De Haes, W., Esser, D., Waschina, S., Lujan, C., Smith, R.L., Scott, T.A., Martinez-Martinez, D., Woodward, O., Bryson, K., Laudes, M., Lieb, W., Houtkooper, R.H., Franke, A., Temmerman, L., Bjedov, I., Cocheme, H.M., Kaleta, C., and Cabreiro, F. (2019). Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy. Cell 178, 1299-1312 e1229. 10.1016/j.cell.2019.08.003.
Scott, T.A., Quintaneiro, L.M., Norvaisas, P., Lui, P.P., Wilson, M.P., Leung, K.Y., Herrera-Dominguez, L., Sudiwala, S., Pessia, A., Clayton, P.T., Bryson, K., Velagapudi, V., Mills, P.B., Typas, A., Greene, N.D.E., and Cabreiro, F. (2017). Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans. Cell 169, 442-456 e418. 10.1016/j.cell.2017.03.040.
Cabreiro, F., Au, C., Leung, K.Y., Vergara-Irigaray, N., Cocheme, H.M., Noori, T., Weinkove, D., Schuster, E., Greene, N.D., and Gems, D. (2013). Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153, 228-239. 10.1016/j.cell.2013.02.035.