Lamming Lab

Perhaps the most important paper of the decade with respect to how cells sense amino acid insufficiency, finally laying to rest the idea that GCN2 is activated by uncharged tRNAs!

Thanks to all our collaborators and colleagues who helped make this possible, including @drcaragreen.bsky.social @mikemacarthur.bsky.social Cholsoon Jang @judisimcox.bsky.social Kristen Malecki and many more!

Diet analysis by Michael MacArthur shows that humans who score highly on the Healthy Eating Index (HEI) score have a lower relative isoleucine intake.

Importantly, by looking across different genetic backgrounds Michaela was able to identify a core set of molecular pathways engaged by IleR, providing new insights into the molecular mechanisms by which it functions.

Michaela showed that isoleucine restriction (IleR) prevents metabolic syndrome in mice fed a Western diet, with beneficial effects on metabolic health across strains and in both sexes. Conversely, excess dietary Ile has strain-specific effects on fat mass and insulin resistance.

We have a thesis defense to celebrate today, but first - we need to celebrate the publication of former student Dr. Michaela Trautman's opus, "Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice" now in Mol Metab! www.sciencedirect.com/science/arti...

Thanks to all our colleagues and collaborators including @drcaragreen.bsky.social, Michelle Sonsalla, Chung-Yang Yeh, @baileyknopf.bsky.social, Teresa Liu, Shoshana Yakar @sadagurski.bsky.social and many more who made this work possible!

Here is the link to the paper, demonstrating that valine restriction has robust effects on healthspan in both sexes and a sex-specific benefit for lifespan in males. www.biorxiv.org/content/10.1...

Our most recent work by graduate student @mariahcalubag
- demonstrating the sex-specific extension of lifespan by valine restriction was presented last week at #ARDD2025 and is now available on bioRxiv! Thanks to Daniela Bakula, @scheibyeknudsenlab.bsky.social, and Alex Zhavoronkov for the invite!

Our results suggest that not only how much we eat - but also when - may influence the development and progression of Alzheimer’s disease.

Reji asked if the benefits of CR for Alzheimer's disease also depend on fasting - and found that YES, a prolonged fast between meals is necessary for the benefits of CR, including reduced Alzheimer’s pathology, improved neuroprotective signaling, and improved cognition.

Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice - Nature Metabolism Pak et al. show that prolonged fasting is required for the effects of calorie restriction on insulin sensitivity, fuel utilization and ageing in mice.

Here we build on previous work by @heidipak.bsky.social who showed that fasting between meals was required for the benefits of a calorie restricted (CR) diet on metabolic health, frailty, and lifespan. www.nature.com/articles/s42...

Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer’s disease - Nature Communications Caloric restriction improves Alzheimer’s Disease outcomes in mice, but this diet not only reduces calories, but imposes a prolonged fast between meals. Here, the authors show this fast is essential to...

"Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer's disease" from first author Dr. Reji Babygirija and with our collabs including @wiscosurgicalmetab.bsky.social is now available online! www.nature.com/articles/s41...

We thank our many colleagues and collaborators including Isaac Grunow, Reji Babygirija, Michelle Sonsalla, @baileyknopf.bsky.social, @wiscosurgicalmetab.bsky.social and Dr. Adam Konopka who helped make this work possible!

These results highlight the direct influence of dietary components on a hallmark of aging and underscore the potential for targeted dietary interventions to modulate senescence.

We further show that hepatic protection from cell senescence is cell-autonomous, with reduced BCAA levels mitigating antimycin-A-induced senescence in cultured hepatocytes.

We find that BCAA restriction not only protects male mice from the metabolic consequences of normal- and high-protein diets, we demonstrate that BCAA restriction reduces hepatic cellular senescence while enhancing senescence in white adipose tissue.

I am pleased to report our new manuscript from graduate student Mariah Calubag and collaborators and colleagues, "Tissue-Specific Effects of Dietary Protein on Cellular Senescence Are Mediated by Branched-Chain Amino Acids" is now available! onlinelibrary.wiley.com/doi/10.1111/...

Thanks as always to our collaborators for helping to make this work possible, including Michelle Sonsalla, @drcaragreen.bsky.social Mariah Calubag, Dr. Chung Yang Yeh, Bailey Knopf, Luigi Puglielli and many more

Here, we find that dietary restriction of either leucine, isoleucine, or valine can slow the progression and development of AD pathology and preserve cognition in this mouse model of the disease. Critically, the impacts of each amino acid on AD pathology and cognition are distinct and sex-specific

Restriction of individual branched-chain amino acids has distinct effects on the development and progression of Alzheimers disease in 3xTg mice Dietary protein is a critical regulator of metabolic health and aging in diverse species. Recent discoveries have determined that many benefits of a low protein diet are the result of reduced consumpt...

Pleased to announce the last major project from former graduate student Dr. Babygirija is now available on biorxiv - "Restriction of individual branched-chain amino acids has distinct effects on the development and progression of Alzheimer's disease in 3xTg mice" www.biorxiv.org/content/10.1...

That’s… not right. The concentration is also way above the (miserable low) solubility limit of rapamycin in water.

Effect of preoperative rapamycin supplementation on perioperative clinical frailty and cognitive performance in a murine model undergoing anesthesia and surgery - Scientific Reports Scientific Reports - Effect of preoperative rapamycin supplementation on perioperative clinical frailty and cognitive performance in a murine model undergoing anesthesia and surgery

Another win for rapamycin: www.nature.com/articles/s41...

Keith came to @americanaging.bsky.social meeting several times, most recently at my invitation, and was always a delight to interact with such a brilliant and kind researcher.

THOMAS BLACKWELL Obituary (1957 - 2025-05-09) - Boston, MA - Boston Globe View THOMAS KEITH BLACKWELL's obituary, send flowers and sign the guestbook.

Sad to learn we lost Keith Blackwell, an unsung hero of the aging field. Keith showed rapamycin extends C. elegans lifespan, that mTORC2 has diet-dependent effects on aging, and linked together skn1 TOR splicing and aging.
www.legacy.com/us/obituarie...

Dietary lipids are largely deposited in skin and rapidly affect insulating properties - Nature Communications The mechanisms underlying the regulation of the skin thermal barrier are poorly understood. Here the authors show that the thermal properties of the skin are reactive to diet and that skin is a target...

Excited to collaborate with Caroline Alexander’s group and @lamminglab.bsky.social demonstrating the contribution of dietary lipids to skin lipids and their insulating properties. Proud of Raghav for leading this collaboration in my lab!
@natcomms.nature.com

www.nature.com/articles/s41...

Thrilled to have our story on the regulation of lysosomal lipids out in @cp-cellmetabolism.bsky.social! The work was led by two outstanding grad students Jess Davidson and Raghav Jain probing mechanistic control of energy expenditure @hhmi.org @uwbiochem.bsky.social

Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV Davidson et al. demonstrated that liver lysosomes orchestrate the metabolic adaptation to cold by rewiring lipid processing. They show that phospholipase A2 group XV (PLA2G15) breaks down bis(monoacylglycerol)phosphate (BMP) lipids to shift lysosomal function and metabolism in response to direct transcription factor EB regulation.

Online now: Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV

Glad to report that this tour de force from our collaborator Caroline Alexander (with a bit of assistance from our lab in the form of Michaela Trautman) is now out: "Dietary lipids are largely deposited in skin and rapidly affect insulating properties" www.nature.com/articles/s41...

A machine learning approach for quantifying age-related histological changes in the mouse kidney - G... The ability to quantify aging-related changes in histological samples is important, as it allows for evaluation of interventions intended to effect health span. We used a machine learning architecture...

New in GeroScience, "A machine learning approach for quantifying age-related histological changes in the mouse kidney" with Susan Sheehan, Seamus Mawe, Mandy Chen,
Ron Korstanje & J Matthew Mahoney 🧪🤝🖥️ 🧬 #machinelearning #ArtificialIntelligence:
link.springer.com/article/10.1...