About

David Walker is a Professor and Vice Chair of Academic Personnel in the Department of Integrative Biology and Physiology at UCLA. He completed his undergraduate degree in Genetics at Queen’s University of Belfast, Northern Ireland, and earned both his MRes and Ph.D. degrees in Genetics from the University of Manchester, UK. His postdoctoral work was conducted at the California Institute of Technology (Caltech), where he received training in Drosophila genetics in the laboratory of Seymour Benzer and in mitochondrial biology in the laboratory of Giuseppe Attardi. He established his independent research group at UCLA in 2007. His research focuses on understanding the mechanisms that cause the deterioration of cellular functions during the aging process. His lab uses the genetics of the fruit fly Drosophila melanogaster to investigate the molecular and cellular mechanisms of aging, aiming to identify novel therapeutic targets to counteract age-related human diseases. His work has contributed to insights into brain aging, mitochondrial defects, autophagy, and intestinal function during aging, with a particular emphasis on how these processes influence healthspan and lifespan.

Research topics

• Biology
• Genetics
• Cell biology
• Immunology
• Neuroscience

Selected publications

• Cytosolic mtDNA and associated EYA-mediated pro-inflammatory signaling modulate healthspan in Drosophila

  Research Square · 2025-10-13

  preprintOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Chronic intestinal immune activation reveals separable impacts of inflammation and barrier loss on hallmarks of ageing

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-15

  preprintOpen access

  Abstract Inflammaging is considered a driver of age-associated pathology across tissues. Similarly, intestinal permeability is a feature of ageing and underlies a range of inflammatory and age-related diseases. Increased intestinal permeability has been described as both a cause and a consequence of inflammation. Both intestinal permeability and inflammation are closely associated with microbial dysbiosis, epithelial dysplasia and mortality but dissecting the complex interplay between these phenotypes remains challenging. Here we genetically induce intestinal immune activation in Drosophila and stratify animals by their intestinal barrier status using the Smurf assay. We demonstrate that intestinal immune activation and barrier failure have distinct impacts on the microbiota. Further, intestinal immune activation drives intestinal barrier failure and mortality even in the absence of the microbiota. Importantly, immune-induced intestinal barrier failure takes time to develop and is closely associated with the onset of mortality. Our work adds to building evidence that the impact of intestinal permeability on the microbiota and on animal health needs to be considered independently of its relationship with inflammation.

  PublisherOA PDFDOI

• Accumulation of F-actin drives brain aging and limits healthspan in Drosophila

  Nature Communications · 2024-10-25 · 21 citations

  articleOpen accessSenior author

  The actin cytoskeleton is a key determinant of cell structure and homeostasis. However, possible tissue-specific changes to actin dynamics during aging, notably brain aging, are not understood. Here, we show that there is an age-related increase in filamentous actin (F-actin) in Drosophila brains, which is counteracted by prolongevity interventions. Critically, decreasing F-actin levels in aging neurons prevents age-onset cognitive decline and extends organismal healthspan. Mechanistically, we show that autophagy, a recycling process required for neuronal homeostasis, is disabled upon actin dysregulation in the aged brain. Remarkably, disrupting actin polymerization in aged animals with cytoskeletal drugs restores brain autophagy to youthful levels and reverses cellular hallmarks of brain aging. Finally, reducing F-actin levels in aging neurons slows brain aging and promotes healthspan in an autophagy-dependent manner. Our data identify excess actin polymerization as a hallmark of brain aging, which can be targeted to reverse brain aging phenotypes and prolong healthspan.

  PublisherOA PDFDOI

• Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria

  Science Advances · 2024-04-03 · 15 citations

  articleOpen access

  The dynamin-related guanosine triphosphatase, Drp1 (encoded by Dnm1l ), plays a central role in mitochondrial fission and is requisite for numerous cellular processes; however, its role in muscle metabolism remains unclear. Here, we show that, among human tissues, the highest number of gene correlations with DNM1L is in skeletal muscle. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and impaired insulin action along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2 normalized complex II activity, lipid oxidation, and insulin action in Drp1-KD myocytes. Drp1 is critical in maintaining mitochondrial complex II assembly, lipid oxidation, and insulin sensitivity, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle metabolism, which is clinically relevant in combatting metabolic-related diseases.

  PublisherOA PDFDOI

• The Impact of Rosemary and Ginger Extracts on Aging and Healthspan in Drosophila

  Aging and Disease · 2024-01-01 · 2 citations

  articleOpen accessSenior author

  Aging leads to a decline in physiological functions and increased risk of mortality, yet therapeutic avenues are limited. Dietary phytochemicals provide an attractive approach to counteract age-related health decline. Here, we have examined the impact of feeding extracts of rosemary and ginger, prepared via three different extraction methods, on markers of aging and healthspan in the fruit fly Drosophila. We observed that certain, but not all, extracts of ginger produce modest prolongevity effects. Feeding extracts of rosemary, produced via the three different methods, each produced prolongevity effects. We observe that feeding combinations of both rosemary and ginger extracts leads to robust lifespan extension. We find that the prolongevity effects of rosemary and ginger extracts are linked to improved intestinal barrier function in aged flies. Importantly, we show that the anti-aging effects observed are not linked to reduced food intake. Interestingly, we observe several instances where the combination of rosemary plus ginger produces effects which are more pronounced or not seen for either extract alone. In terms of cellular hallmarks of aging, rosemary plus ginger feeding leads to AMPK activation and improved markers of autophagy and proteostasis in aged flies. Furthermore, feeding the combination of rosemary plus ginger feeding improves cognitive function in aged flies. Our results demonstrate that rosemary and ginger extracts can counteract aging and prolong healthspan in flies.

  PublisherOA PDFDOI

• Redundancy of p75NTR neurotrophin receptor function in development, growth and fertility in the rat

  Transgenic Research · 2024-07-09 · 3 citations

  articleOpen access

  Abstract The p75NTR neurotrophin receptor has positive and negative roles regulating cell survival in the nervous system. Unambiguous interpretation of p75NTR function in vivo has been complicated, however, by residual expression of alternate forms of p75NTR protein in initial p75NTR knock-out mouse models. As rats are the preferred rodent for studying brain and behaviour, and to simplify interpretation of the knock-out phenotype, we report here the generation of a mutant rat devoid of the p75NTR protein. TALEN-mediated recombination in embryonic stem cells (ESCs) was used to flank exon 2 of p75NTR with Lox P sites and produce transgenic rats carrying either un-recombined floxed p75NTR Ex2-fl , or recombined, exon-2 deleted p75NTR Ex2-Δ alleles. Crossing p75NTR Ex2-fl rats with a Cre -deleter strain efficiently removed exon 2 in vivo. Excision of exon 2 causes a frameshift after p75NTR Gly23 and eliminated p75NTR protein expression. Rats lacking p75NTR were healthy, fertile, and histological analysis did not reveal significant changes in cellular density or overall structure in their brains. p75NTR function is therefore largely dispensable for normal development, growth and basal homeostasis in the rat. However, the availability of constitutive and conditional p75NTR Ex2-Δ rats provides new opportunities to investigate specific roles of p75NTR upon injury and during tissue repair.

  PublisherOA PDFDOI

• <i>p75NTR</i> neurotrophin receptor function is redundant for development, growth and fertility in the rat

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-12-27

  preprintOpen access

  Abstract The p75NTR neurotrophin receptor has positive and negative roles regulating cell survival in the nervous system. Unambiguous interpretation of p75NTR function in vivo has been complicated, however, by residual expression of alternate forms of p75NTR protein in initial p75NTR knock-out mouse models. As rats are the preferred rodent for studying brain and behaviour, and to simplify interpretation of the knock-out phenotype, we report here the generation of a mutant rat devoid of the p75NTR protein. TALEN-mediated recombination in embryonic stem cells (ESCs) was used to flank exon 2 of p75NTR with Lox P sites and produce transgenic rats carrying either un-recombined floxed p75NTR Ex 2 -fl , or recombined, exon-2 deleted p75NTR Ex 2 - Δ alleles. Crossing p75NTR Ex 2 -fl rats with a Cre -deleter strain efficiently removed exon 2 in vivo . Excision of exon 2 causes a frameshift after p75NTR Gly23 and eliminated p75NTR protein expression. Rats lacking p75NTR were healthy, fertile, and histological analysis did not reveal significant changes in cellular density or overall structure in their brains. Thus, p75NTR function appears largely dispensable for normal development, growth and basal homeostasis in the rat. The availability of constitutive and conditional p75NTR Ex2-Δ rats should, however, provide new opportunities to investigate specific roles of p75NTR upon injury and during regeneration.

  PublisherOA PDFDOI

• Intestinal barrier dysfunction: an evolutionarily conserved hallmark of aging

  Disease Models & Mechanisms · 2023 · 78 citations

  Senior authorCorresponding
  • Biology
  • Immunology
  • Genetics

  A major challenge in the biology of aging is to understand how specific age-onset pathologies relate to the overall health of the organism. The integrity of the intestinal epithelium is essential for the wellbeing of the organism throughout life. In recent years, intestinal barrier dysfunction has emerged as an evolutionarily conserved feature of aged organisms, as reported in worms, flies, fish, rodents and primates. Moreover, age-onset intestinal barrier dysfunction has been linked to microbial alterations, elevated immune responses, metabolic alterations, systemic health decline and mortality. Here, we provide an overview of these findings. We discuss early work in the Drosophila model that sets the stage for examining the relationship between intestinal barrier integrity and systemic aging, then delve into research in other organisms. An emerging concept, supported by studies in both Drosophila and mice, is that directly targeting intestinal barrier integrity is sufficient to promote longevity. A better understanding of the causes and consequences of age-onset intestinal barrier dysfunction has significant relevance to the development of interventions to promote healthy aging.

  PublisherDOI

• Widespread RNA hypoediting in schizophrenia and its relevance to mitochondrial function

  Science Advances · 2023-04-07 · 29 citations

  articleOpen access

  RNA editing, the endogenous modification of nucleic acids, is known to be altered in genes with important neurological function in schizophrenia (SCZ). However, the global profile and molecular functions of disease-associated RNA editing remain unclear. Here, we analyzed RNA editing in postmortem brains of four SCZ cohorts and uncovered a significant and reproducible trend of hypoediting in patients of European descent. We report a set of SCZ-associated editing sites via WGCNA analysis, shared across cohorts. Using massively parallel reporter assays and bioinformatic analyses, we observed that differential 3′ untranslated region (3′UTR) editing sites affecting host gene expression were enriched for mitochondrial processes. Furthermore, we characterized the impact of two recoding sites in the mitofusin 1 ( MFN1 ) gene and showed their functional relevance to mitochondrial fusion and cellular apoptosis. Our study reveals a global reduction of editing in SCZ and a compelling link between editing and mitochondrial function in the disease.

  PublisherOA PDFDOI

• Accumulation of F-actin drives brain aging and limits healthspan in Drosophila

  Research Square · 2023-08-01 · 1 citations

  preprintOpen access1st authorCorresponding

  Abstract The actin cytoskeleton is a key determinant of cell and tissue homeostasis. However, tissue-specific roles for actin dynamics in aging, notably brain aging, are not understood. Here, we show that there is an age-related increase in filamentous actin (F-actin) in Drosophila brains, which is counteracted by prolongevity interventions. Critically, modulating F-actin levels in aging neurons prevents age-onset cognitive decline and extends organismal healthspan. Mechanistically, we show that autophagy, a recycling process required for neuronal homeostasis, is disabled upon actin dysregulation in the aged brain. Remarkably, disrupting actin polymerization in aged animals with cytoskeletal drugs restores brain autophagy to youthful levels and reverses cellular hallmarks of brain aging. Finally, reducing F-actin levels in aging neurons slows brain aging and promotes healthspan in an autophagy-dependent manner. Our data identify excess actin polymerization as a hallmark of brain aging, which can be targeted to reverse brain aging phenotypes and prolong healthspan.

  PublisherOA PDFDOI

Recent grants

• Role of Mitochondrial Homeostasis in Animal Aging

  NIH · $5.3M · 2010–2027

• Role of Intestinal Homeostasis in Organismal Aging

  NIH · $2.4M · 2015–2027

• Metabolic regulation of stem cell behavior and longevity

  NIH · $3.0M · 2012–2019

Frequent coauthors

• Michaël Rera

  Institut Jacques Monod

  11 shared

• Carina Mallard

  University of Gothenburg

  10 shared

• Henrik Hagberg

  St Thomas' Hospital

  10 shared

• Donna M. Ferriero

  University of California, San Francisco

  10 shared

• Margie Castillo‐Melendez

  Hudson Institute of Medical Research

  10 shared

• Rosa Méndez

  Texas A&M University

  9 shared

• Grace Tharmarajah

  Precision Nanosystems (Canada)

  9 shared

• Y. Fernández

  TTI (Spain)

  9 shared

Labs

• David Walker LabPI

Education

• Ph.D., Biology

  University of California, Los Angeles

  1995

• B.S., Biology

  University of California, Los Angeles

  1990