Guidelines for minimal information on cellular senescence experimentation in vivo.

Cellular senescence is a cell fate triggered in response to stress and is characterized by stable cell-cycle arrest and a hypersecretory state. It has diverse biological roles, ranging from tissue repair to chronic disease. The development of new tools to study senescence in vivo has paved the way for uncovering its physiological and pathological roles and testing senescent cells as a therapeutic target. However, the lack of specific and broadly applicable markers makes it difficult to identify and characterize senescent cells in tissues and living organisms. To address this, we provide practical guidelines called "minimum information for cellular senescence experimentation in vivo" (MICSE). It presents an overview of senescence markers in rodent tissues, transgenic models, non-mammalian systems, human tissues, and tumors and their use in the identification and specification of senescent cells. These guidelines provide a uniform, state-of-the-art, and accessible toolset to improve our understanding of cellular senescence in vivo.

Human population history at the crossroads of East and Southeast Asia since 11,000 years ago.

Past human genetic diversity and migration between southern China and Southeast Asia have not been well characterized, in part due to poor preservation of ancient DNA in hot and humid regions. We sequenced 31 ancient genomes from southern China (Guangxi and Fujian), including two ∼12,000- to 10,000-year-old individuals representing the oldest humans sequenced from southern China. We discovered a deeply diverged East Asian ancestry in the Guangxi region that persisted until at least 6,000 years ago. We found that ∼9,000- to 6,000-year-old Guangxi populations were a mixture of local ancestry, southern ancestry previously sampled in Fujian, and deep Asian ancestry related to Southeast Asian Hòabìnhian hunter-gatherers, showing broad admixture in the region predating the appearance of farming. Historical Guangxi populations dating to ∼1,500 to 500 years ago are closely related to Tai-Kadai and Hmong-Mien speakers. Our results show heavy interactions among three distinct ancestries at the crossroads of East and Southeast Asia.

Neuronal Computation Underlying Inferential Reasoning in Humans and Mice.

Every day we make decisions critical for adaptation and survival. We repeat actions with known consequences. But we also draw on loosely related events to infer and imagine the outcome of entirely novel choices. These inferential decisions are thought to engage a number of brain regions; however, the underlying neuronal computation remains unknown. Here, we use a multi-day cross-species approach in humans and mice to report the functional anatomy and neuronal computation underlying inferential decisions. We show that during successful inference, the mammalian brain uses a hippocampal prospective code to forecast temporally structured learned associations. Moreover, during resting behavior, coactivation of hippocampal cells in sharp-wave/ripples represent inferred relationships that include reward, thereby "joining-the-dots" between events that have not been observed together but lead to profitable outcomes. Computing mnemonic links in this manner may provide an important mechanism to build a cognitive map that stretches beyond direct experience, thus supporting flexible behavior.

Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy.

Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies. VIDEO ABSTRACT.

Screening for lung cancer: 2023 guideline update from the American Cancer Society.

Lung cancer is the leading cause of mortality and person-years of life lost from cancer among US men and women. Early detection has been shown to be associated with reduced lung cancer mortality. Our objective was to update the American Cancer Society (ACS) 2013 lung cancer screening (LCS) guideline for adults at high risk for lung cancer. The guideline is intended to provide guidance for screening to health care providers and their patients who are at high risk for lung cancer due to a history of smoking. The ACS Guideline Development Group (GDG) utilized a systematic review of the LCS literature commissioned for the US Preventive Services Task Force 2021 LCS recommendation update; a second systematic review of lung cancer risk associated with years since quitting smoking (YSQ); literature published since 2021; two Cancer Intervention and Surveillance Modeling Network-validated lung cancer models to assess the benefits and harms of screening; an epidemiologic and modeling analysis examining the effect of YSQ and aging on lung cancer risk; and an updated analysis of benefit-to-radiation-risk ratios from LCS and follow-up examinations. The GDG also examined disease burden data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Formulation of recommendations was based on the quality of the evidence and judgment (incorporating values and preferences) about the balance of benefits and harms. The GDG judged that the overall evidence was moderate and sufficient to support a strong recommendation for screening individuals who meet the eligibility criteria. LCS in men and women aged 50-80 years is associated with a reduction in lung cancer deaths across a range of study designs, and inferential evidence supports LCS for men and women older than 80 years who are in good health. The ACS recommends annual LCS with low-dose computed tomography for asymptomatic individuals aged 50-80 years who currently smoke or formerly smoked and have a ≥20 pack-year smoking history (strong recommendation, moderate quality of evidence). Before the decision is made to initiate LCS, individuals should engage in a shared decision-making discussion with a qualified health professional. For individuals who formerly smoked, the number of YSQ is not an eligibility criterion to begin or to stop screening. Individuals who currently smoke should receive counseling to quit and be connected to cessation resources. Individuals with comorbid conditions that substantially limit life expectancy should not be screened. These recommendations should be considered by health care providers and adults at high risk for lung cancer in discussions about LCS. If fully implemented, these recommendations have a high likelihood of significantly reducing death and suffering from lung cancer in the United States.

Ex vivo reconstitution of fetal oocyte development in humans and cynomolgus monkeys.

In vitro oogenesis is key to elucidating the mechanism of human female germ-cell development and its anomalies. Accordingly, pluripotent stem cells have been induced into primordial germ cell-like cells and into oogonia with epigenetic reprogramming, yet further reconstitutions remain a challenge. Here, we demonstrate ex vivo reconstitution of fetal oocyte development in both humans and cynomolgus monkeys (Macaca fascicularis). With an optimized culture of fetal ovary reaggregates over three months, human and monkey oogonia enter and complete the first meiotic prophase to differentiate into diplotene oocytes that form primordial follicles, the source for oogenesis in adults. The cytological and transcriptomic progressions of fetal oocyte development in vitro closely recapitulate those in vivo. A comparison of single-cell transcriptomes among humans, monkeys, and mice unravels primate-specific and conserved programs driving fetal oocyte development, the former including a distinct transcriptomic transformation upon oogonia-to-oocyte transition and the latter including two active X chromosomes with little X-chromosome upregulation. Our study provides a critical step forward for realizing human in vitro oogenesis and uncovers salient characteristics of fetal oocyte development in primates.

Physiological role of cytokines in the regulation of mammalian metabolism.

The innate cytokine system is involved in the response to excessive food intake. In this review, we highlight recent advances in our understanding of the physiological role of three prominent cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF), in mammalian metabolic regulation. This recent research highlights the pleiotropic and context-dependent functions in the immune-metabolic interplay. IL-1ß is activated in response to overloaded mitochondrial metabolism, stimulates insulin secretion, and allocates energy to immune cells. IL-6 is released by contracting skeletal muscle and adipose tissue and directs energy from storing tissues to consuming tissues. TNF induces insulin resistance and prevents ketogenesis. Additionally, the therapeutic potential of modulating the activity of each cytokine is discussed.

Application of New Lineage Tracing Techniques in Cardiovascular Development and Physiology.

Cardiovascular disease has been the leading cause of mortality and morbidity worldwide in the past 3 decades. Multiple cell lineages undergo dynamic alternations in gene expression, cell state determination, and cell fate conversion to contribute, adapt, and even modulate the pathophysiological processes during disease progression. There is an urgent need to understand the intricate cellular and molecular underpinnings of cardiovascular cell development in homeostasis and pathogenesis. Recent strides in lineage tracing methodologies have revolutionized our understanding of cardiovascular biology with the identification of new cellular origins, fates, plasticity, and heterogeneity within the cardiomyocyte, endothelial, and mesenchymal cell populations. In this review, we introduce the new technologies for lineage tracing of cardiovascular cells and summarize their applications in studying cardiovascular development, diseases, repair, and regeneration.

Genomic perspectives on human dispersals during the Holocene.

Nearly 20 y ago, Jared Diamond and Peter Bellwood reviewed the evidence for the associated spread of farming and large language families by the demographic expansions of farmers. Since then, advances in obtaining and analyzing genomic data from modern and ancient populations have transformed our knowledge of human dispersals during the Holocene. Here, we provide an overview of Holocene dispersals in the light of genomic evidence and conclude that they have a complex history. Even when there is a demonstrated connection between a demographic expansion of people, the spread of agriculture, and the spread of a particular language family, the outcome in the results of contact between expanding and resident groups is highly variable. Further research is needed to identify the factors and social circumstances that have influenced this variation and complex history.

Large-scale functional screen identifies genetic variants with splicing effects in modern and archaic humans.

Humans coexisted and interbred with other hominins which later became extinct. These archaic hominins are known to us only through fossil records and for two cases, genome sequences. Here, we engineer Neanderthal and Denisovan sequences into thousands of artificial genes to reconstruct the pre-mRNA processing patterns of these extinct populations. Of the 5,169 alleles tested in this massively parallel splicing reporter assay (MaPSy), we report 962 exonic splicing mutations that correspond to differences in exon recognition between extant and extinct hominins. Using MaPSy splicing variants, predicted splicing variants, and splicing quantitative trait loci, we show that splice-disrupting variants experienced greater purifying selection in anatomically modern humans than that in Neanderthals. Adaptively introgressed variants were enriched for moderate-effect splicing variants, consistent with positive selection for alternative spliced alleles following introgression. As particularly compelling examples, we characterized a unique tissue-specific alternative splicing variant at the adaptively introgressed innate immunity gene TLR1, as well as a unique Neanderthal introgressed alternative splicing variant in the gene HSPG2 that encodes perlecan. We further identified potentially pathogenic splicing variants found only in Neanderthals and Denisovans in genes related to sperm maturation and immunity. Finally, we found splicing variants that may contribute to variation among modern humans in total bilirubin, balding, hemoglobin levels, and lung capacity. Our findings provide unique insights into natural selection acting on splicing in human evolution and demonstrate how functional assays can be used to identify candidate causal variants underlying differences in gene regulation and phenotype.