Aging, Lifespan & Longevity

Supervised mutational signatures for obesity and other tissue-specific etiological factors in cancer.

Elife. 2021 Jan 25;10:

Authors: Afsari B, Kuo A, Zhang Y, Li L, Lahouel K, Danilova L, Favorov A, Rosenquist TA, Grollman AP, Kinzler KW, Cope L, Vogelstein B, Tomasetti C

Abstract
Determining the etiologic basis of the mutations that are responsible for cancer is one of the fundamental challenges in modern cancer research. Different mutational processes induce different types of DNA mutations, providing 'mutational signatures' that have led to key insights into cancer etiology. The most widely used signatures for assessing genomic data are based on unsupervised patterns that are then retrospectively correlated with certain features of cancer. We show here that supervised machine-learning techniques can identify signatures, called SuperSigs, that are more predictive than those currently available. Surprisingly, we found that aging yields different SuperSigs in different tissues, and the same is true for environmental exposures. We were able to discover SuperSigs associated with obesity, the most important lifestyle factor contributing to cancer in Western populations.

PMID: 33491650 [PubMed - as supplied by publisher]

A dietary sterol trade-off determines lifespan responses to dietary restriction in Drosophila melanogaster females.

Elife. 2021 Jan 26;10:

Authors: Zanco B, Mirth CK, Sgrò CM, Piper MD

Abstract
Diet plays a significant role in maintaining lifelong health. In particular, lowering the dietary protein: carbohydrate ratio can improve lifespan. This has been interpreted as a direct effect of these macronutrients on physiology. Using Drosophila melanogaster, we show that the role of protein and carbohydrate on lifespan is indirect, acting by altering the partitioning of limiting amounts of dietary sterols between reproduction and lifespan. Shorter lifespans in flies fed on high protein: carbohydrate diets can be rescued by supplementing their food with cholesterol. Not only does this fundamentally alter the way we interpret the mechanisms of lifespan extension by dietary restriction, these data highlight the important principle that life histories can be affected by nutrient-dependent trade-offs that are indirect and independent of the nutrients (often macronutrients) that are the focus of study. This brings us closer to understanding the mechanistic basis of dietary restriction.

PMID: 33494859 [PubMed - in process]

Replication-independent instability of Friedreich's ataxia GAA repeats during chronological aging.

Proc Natl Acad Sci U S A. 2021 Feb 02;118(5):

Authors: Neil AJ, Hisey JA, Quasem I, McGinty RJ, Hitczenko M, Khristich AN, Mirkin SM

Abstract
Nearly 50 hereditary diseases result from the inheritance of abnormally long repetitive DNA microsatellites. While it was originally believed that the size of inherited repeats is the key factor in disease development, it has become clear that somatic instability of these repeats throughout an individual's lifetime strongly contributes to disease onset and progression. Importantly, somatic instability is commonly observed in terminally differentiated, postmitotic cells, such as neurons. To unravel the mechanisms of repeat instability in nondividing cells, we created an experimental system to analyze the mutability of Friedreich's ataxia (GAA)n repeats during chronological aging of quiescent Saccharomyces cerevisiae Unexpectedly, we found that the predominant repeat-mediated mutation in nondividing cells is large-scale deletions encompassing parts, or the entirety, of the repeat and adjacent regions. These deletions are caused by breakage at the repeat mediated by mismatch repair (MMR) complexes MutSβ and MutLα and DNA endonuclease Rad1, followed by end-resection by Exo1 and repair of the resulting double-strand breaks (DSBs) via nonhomologous end joining. We also observed repeat-mediated gene conversions as a result of DSB repair via ectopic homologous recombination during chronological aging. Repeat expansions accrue during chronological aging as well-particularly in the absence of MMR-induced DSBs. These expansions depend on the processivity of DNA polymerase δ while being counteracted by Exo1 and MutSβ, implicating nick repair. Altogether, these findings show that the mechanisms and types of (GAA)n repeat instability differ dramatically between dividing and nondividing cells, suggesting that distinct repeat-mediated mutations in terminally differentiated somatic cells might influence Friedreich's ataxia pathogenesis.

PMID: 33495349 [PubMed - in process]

Thermal acclimation of tropical coral reef fishes to global heat waves.

Elife. 2021 Jan 26;10:

Authors: Johansen JL, Nadler LE, Habary A, Bowden AJ, Rummer J

Abstract
As climate-driven heat waves become more frequent and intense, there is increasing urgency to understand how thermally sensitive species are responding. Acute heating events lasting days to months may elicit acclimation responses to improve performance and survival. However, the coordination of acclimation responses remains largely unknown for most stenothermal species. We documented the chronology of 18 metabolic and cardiorespiratory changes that occur in the gills, blood, spleen, and muscles when tropical coral reef fishes are thermally stressed (+3.0°C above ambient). Using representative coral reef fishes (Caesio cuning and Cheilodipterus quinquelineatus) separated by >100 million years of evolution and with stark differences in major life-history characteristics (i.e. lifespan, habitat use, mobility, etc.), we show that exposure duration illicited coordinated responses in 13 tissue and organ systems over 5 weeks. The onset and duration of biomarker responses differed between species, with C. cuning - an active, mobile species - initiating acclimation responses to unavoidable thermal stress within the first week of heat exposure; conversely, C. quinquelineatus - a sessile, territorial species - exhibited comparatively reduced acclimation responses that were delayed through time. Seven biomarkers, including red muscle citrate synthase and lactate dehydrogenase activities, blood glucose and hemoglobin concentrations, spleen somatic index, and gill lamellar perimeter and width, proved critical in evaluating acclimation progression and completion, as these provided consistent evaluation of thermal responses across species.

PMID: 33496262 [PubMed - in process]

Targeting age-specific changes in CD4+ T cell metabolism ameliorates alloimmune responses and prolongs graft survival.

Aging Cell. 2021 Jan 26;:e13299

Authors: Nian Y, Iske J, Maenosono R, Minami K, Heinbokel T, Quante M, Liu Y, Azuma H, Yang J, Abdi R, Zhou H, Elkhal A, Tullius SG

Abstract
Age impacts alloimmunity. Effects of aging on T-cell metabolism and the potential to interfere with immunosuppressants have not been explored yet. Here, we dissected metabolic pathways of CD4+ and CD8+ T cells in aging and offer novel immunosuppressive targets. Upon activation, CD4+ T cells from old mice failed to exhibit adequate metabolic reprogramming resulting into compromised metabolic pathways, including oxidative phosphorylation (OXPHOS) and glycolysis. Comparable results were also observed in elderly human patients. Although glutaminolysis remained the dominant and age-independent source of mitochondria for activated CD4+ T cells, old but not young CD4+ T cells relied heavily on glutaminolysis. Treating young and old murine and human CD4+ T cells with 6-diazo-5-oxo-l-norleucine (DON), a glutaminolysis inhibitor resulted in significantly reduced IFN-γ production and compromised proliferative capacities specifically of old CD4+ T cells. Of translational relevance, old and young mice that had been transplanted with fully mismatched skin grafts and treated with DON demonstrated dampened Th1- and Th17-driven alloimmune responses. Moreover, DON diminished cytokine production and proliferation of old CD4+ T cells in vivo leading to a significantly prolonged allograft survival specifically in old recipients. Graft prolongation in young animals, in contrast, was only achieved when DON was applied in combination with an inhibition of glycolysis (2-deoxy-d-glucose, 2-DG) and OXPHOS (metformin), two alternative metabolic pathways. Notably, metabolic treatment had not been linked to toxicities. Remarkably, immunosuppressive capacities of DON were specific to CD4+ T cells as adoptively transferred young CD4+ T cells prevented immunosuppressive capacities of DON on allograft survival in old recipients. Depletion of CD8+ T cells did not alter transplant outcomes in either young or old recipients. Taken together, our data introduce an age-specific metabolic reprogramming of CD4+ T cells. Targeting those pathways offers novel and age-specific approaches for immunosuppression.

PMID: 33497523 [PubMed - as supplied by publisher]

Metabolic regulation of telomere silencing by SESAME complex-catalyzed H3T11 phosphorylation.

Nat Commun. 2021 01 26;12(1):594

Authors: Zhang S, Yu X, Zhang Y, Xue X, Yu Q, Zha Z, Gogol M, Workman JL, Li S

Abstract
Telomeres are organized into a heterochromatin structure and maintenance of silent heterochromatin is required for chromosome stability. How telomere heterochromatin is dynamically regulated in response to stimuli remains unknown. Pyruvate kinase Pyk1 forms a complex named SESAME (Serine-responsive SAM-containing Metabolic Enzyme complex) to regulate gene expression by phosphorylating histone H3T11 (H3pT11). Here, we identify a function of SESAME in regulating telomere heterochromatin structure. SESAME phosphorylates H3T11 at telomeres, which maintains SIR (silent information regulator) complex occupancy at telomeres and protects Sir2 from degradation by autophagy. Moreover, SESAME-catalyzed H3pT11 directly represses autophagy-related gene expression to further prevent autophagy-mediated Sir2 degradation. By promoting H3pT11, serine increases Sir2 protein levels and enhances telomere silencing. Loss of H3pT11 leads to reduced Sir2 and compromised telomere silencing during chronological aging. Together, our study provides insights into dynamic regulation of silent heterochromatin by histone modifications and autophagy in response to cell metabolism and aging.

PMID: 33500413 [PubMed - indexed for MEDLINE]

A new era for research into aging.

Elife. 2021 Jan 28;10:

Authors: Kaeberlein M, Tyler JK

Abstract
eLife is publishing a special issue on aging, geroscience and longevity to mark the rapid progress made in this field over the past decade, both in terms of mechanistic understanding and translational approaches that are poised to have clinical impact on age-related diseases.

PMID: 33504426 [PubMed - in process]

Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells.

Proc Natl Acad Sci U S A. 2021 Feb 16;118(7):

Authors: Pienta KJ, Hammarlund EU, Brown JS, Amend SR, Axelrod RM

Abstract
We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to protect DNA integrity and ensure cell survival. Upon removal of stress, e.g., chemotherapy, PACCs undergo depolyploidization and generate resistant progeny that make up the bulk of cancer cells within a tumor.

PMID: 33504594 [PubMed - in process]

Niche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1.

Nat Commun. 2021 01 27;12(1):608

Authors: Renders S, Svendsen AF, Panten J, Rama N, Maryanovich M, Sommerkamp P, Ladel L, Redavid AR, Gibert B, Lazare S, Ducarouge B, Schönberger K, Narr A, Tourbez M, Dethmers-Ausema B, Zwart E, Hotz-Wagenblatt A, Zhang D, Korn C, Zeisberger P, Przybylla A, Sohn M, Mendez-Ferrer S, Heikenwälder M, Brune M, Klimmeck D, Bystrykh L, Frenette PS, Mehlen P, de Haan G, Cabezas-Wallscheid N, Trumpp A

Abstract
Haematopoietic stem cells (HSCs) are characterized by their self-renewal potential associated to dormancy. Here we identify the cell surface receptor neogenin-1 as specifically expressed in dormant HSCs. Loss of neogenin-1 initially leads to increased HSC expansion but subsequently to loss of self-renewal and premature exhaustion in vivo. Its ligand netrin-1 induces Egr1 expression and maintains quiescence and function of cultured HSCs in a Neo1 dependent manner. Produced by arteriolar endothelial and periarteriolar stromal cells, conditional netrin-1 deletion in the bone marrow niche reduces HSC numbers, quiescence and self-renewal, while overexpression increases quiescence in vivo. Ageing associated bone marrow remodelling leads to the decline of netrin-1 expression in niches and a compensatory but reversible upregulation of neogenin-1 on HSCs. Our study suggests that niche produced netrin-1 preserves HSC quiescence and self-renewal via neogenin-1 function. Decline of netrin-1 production during ageing leads to the gradual decrease of Neo1 mediated HSC self-renewal.

PMID: 33504783 [PubMed - indexed for MEDLINE]

A thin mantle transition zone beneath the equatorial Mid-Atlantic Ridge.

Nature. 2021 Jan;589(7843):562-566

Authors: Agius MR, Rychert CA, Harmon N, Tharimena S, Kendall JM

Abstract
The location and degree of material transfer between the upper and lower mantle are key to the Earth's thermal and chemical evolution. Sinking slabs and rising plumes are generally accepted as locations of transfer1,2, whereas mid-ocean ridges are not typically assumed to have a role3. However, tight constraints from in situ measurements at ridges have proved to be challenging. Here we use receiver functions that reveal the conversion of primary to secondary seismic waves to image the discontinuities that bound the mantle transition zone, using ocean bottom seismic data from the equatorial Mid-Atlantic Ridge. Our images show that the seismic discontinuity at depths of about 660 kilometres is broadly uplifted by 10 ± 4 kilometres over a swath about 600 kilometres wide and that the 410-kilometre discontinuity is depressed by 5 ± 4 kilometres. This thinning of the mantle transition zone is coincident with slow shear-wave velocities in the mantle, from global seismic tomography4-7. In addition, seismic velocities in the mantle transition zone beneath the Mid-Atlantic Ridge are on average slower than those beneath older Atlantic Ocean seafloor. The observations imply material transfer from the lower to the upper mantle-either continuous or punctuated-that is linked to the Mid-Atlantic Ridge. Given the length and longevity of the mid-ocean ridge system, this implies that whole-mantle convection may be more prevalent than previously thought, with ridge upwellings having a role in counterbalancing slab downwellings.

PMID: 33505039 [PubMed - in process]