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To elucidate whether Bronze Age population dispersals from the Eurasian Steppe to South Asia contributed to the gene pool of Indo-Iranian-speaking groups, we analyzed 19,568 mitochondrial DNA (mtDNA) sequences from northern Pakistani and surrounding populations, including 213 newly generated mitochondrial genomes (mitogenomes) from Iranian and Dardic groups, both speakers from the ancient Indo-Iranian branch in northern Pakistan. Our results showed that 23% of mtDNA lineages with west Eurasian origin arose in situ in northern Pakistan since ~5000 years ago (kya), a time depth very close to the documented Indo-European dispersals into South Asia during the Bronze Age. Together with ancient mitogenomes from western Eurasia since the Neolithic, we identified five haplogroups (~8.4% of maternal gene pool) with roots in the Steppe region and subbranches arising (age ~5-2 kya old) in northern Pakistan as genetic legacies of Indo-Iranian speakers. Some of these haplogroups, such as W3a1b that have been found in the ancient samples from the late Bronze Age to the Iron Age period individuals of Swat Valley northern Pakistan, even have sub-lineages (age ~4 kya old) in the southern subcontinent, consistent with the southward spread of Indo-Iranian languages. By showing that substantial genetic components of Indo-Iranian speakers in northern Pakistan can be traced to Bronze Age in the Steppe region, our study suggests a demographic link with the spread of Indo-Iranian languages, and further highlights the corridor role of northern Pakistan in the southward dispersal of Indo-Iranian-speaking groups.

Cellular senescence is a fundamental cell fate playing a significant role throughout the natural aging process. However, the molecular determinants distinguishing senescence from other cell-cycle arrest states such as quiescence and post-mitotic state, and the specified mechanisms underlying cell-fate decisions towards senescence versus cell death in response to cellular stress stimuli remain less understood. Employing multi-omics approaches, we revealed that switching off the specific mitochondrial processing machinery involving the peptidase IMMP2L serves as the foundation of the senescence program, which was also observed during the mammalian aging process. Mechanistically, we demonstrate that IMMP2L processes and thus activates at least two substrates, mitochondrial metabolic enzyme glycerol-3-phosphate dehydrogenase (GPD2) and cell death regulator apoptosis-inducing factor (AIF). For cells destined to senesce, concerted shutdown of the IMMP2L-GPD2 and IMMP2L-AIF signaling axes collaboratively drives the senescent process by reprogramming mitochondria-associated redox status, phospholipid metabolism and signaling network, and simultaneously blocking cell death under oxidative stress conditions.

The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (P(meta)=5.0 × 10(-4)) and rs800292 (P(meta)=1.3 × 10(-5)) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16 795 controls). Rs1061170 (P=2.5 × 10(-3)) and rs800292 (P=4.7 × 10(-4)) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and Aβ levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress.

Centenarians are a good healthy aging model. Interestingly, centenarians' offspring are prone to achieve longevity. Here we recruited 60 longevity families and investigated the blood biochemical indexes of family members to seek candidate factors associated with familial longevity. First, associations of blood indexes with age were tested. Second, associations of blood parameters in centenarians (CEN) with their first generation of offspring (F1) and F1 spouses (F1SP) were analyzed. Third, genes involved in regulating target factors were investigated. We found that total cholesterol (TC) and triglyceride (TG) increased with age (20-80 years), but decreased in CEN. Similarly, blood urea nitrogen (BUN) and blood creatinine (BCr) increased with age (20-80 years), but were maintained on a plateau in CEN. Importantly, we first revealed dual changes in blood pressure, i.e., decreased diastolic blood pressure but increased systolic blood pressure in CEN, which associated with altered CST3 expression. Genetic analysis revealed a significant association of blood uric acid (BUA) and BCr in CEN with F1 but not with F1SP, suggesting they may be heritable traits. Taken together, our results suggest serum lipids, kidney function and especially diastolic pressure rather than systolic pressure were improved in CEN or their offspring, suggesting these factors may play an important role in familial longevity.

Hypertension is the most common and lethal risk factor for cardiovascular disease (CVD). Numerous variants have been associated with hypertension, however, most of which failed to get replication due to ethnic differences. In this study, we analyzed associations of 10 newly reported single nucleotide polymorphisms (SNPs) in Europeans with hypertension in Chinese. A total of 1766 samples consisting of 880 subjects with hypertension and 886 controls were collected and the SNPs were genotyped using multiple assays based on the SNaPshot mini-sequencing approach. Our results revealed a significant genotypic association of rs4746172 of VCL with hypertension with a lower frequency of minor allele in male subjects (OR = 0.70, 95% CI: 0.54-0.92, p = 0.011) but not in females. To validate the result, we genotyped the SNPs in another Chinese population with 546 individuals, and got a consistent association for the rs4746172 (OR = 0.56, 95% CI: 0.38-0.82, p = 2.4 × 10(-3)) in males. The VCL-encoding protein was involved in cardiomyopathy that associated with hypertension, therefore our results suggest the rs4746172 of VCL may be a novel target for clinical interventions to reduce CVD risk by regulating blood pressure in male Chinese.

Given the existence of plenty of river valleys connecting Southeast and East Asia, it is possible that some inland route(s) might have been adopted by the initial settlers to migrate into the interior of East Asia. Here we analyzed mitochondrial DNA (mtDNA) HVS variants of 845 newly collected individuals from 14 Myanmar populations and 5,907 published individuals from 115 populations from Myanmar and its surroundings. Enrichment of basal lineages with the highest genetic diversity in Myanmar suggests that Myanmar was likely one of the differentiation centers of the early modern humans. Intriguingly, some haplogroups were shared merely between Myanmar and southwestern China, hinting certain genetic connection between both regions. Further analyses revealed that such connection was in fact attributed to both recent gene flow and certain ancient dispersals from Myanmar to southwestern China during 25-10 kya, suggesting that, besides the coastal route, the early modern humans also adopted an inland dispersal route to populate the interior of East Asia.

Contemporary Jews retain a genetic imprint from their Near Eastern ancestry, but obtained substantial genetic components from their neighboring populations during their history. Whether they received any genetic contribution from the Far East remains unknown, but frequent communication with the Chinese has been observed since the Silk Road period. To address this issue, mitochondrial DNA (mtDNA) variation from 55,595 Eurasians are analyzed. The existence of some eastern Eurasian haplotypes in eastern Ashkenazi Jews supports an East Asian genetic contribution, likely from Chinese. Further evidence indicates that this connection can be attributed to a gene flow event that occurred less than 1.4 kilo-years ago (kya), which falls within the time frame of the Silk Road scenario and fits well with historical records and archaeological discoveries. This observed genetic contribution from Chinese to Ashkenazi Jews demonstrates that the historical exchange between Ashkenazim and the Far East was not confined to the cultural sphere but also extended to an exchange of genes.

Domestic chickens (Gallus gallus domesticus) fulfill various roles ranging from food and entertainment to religion and ornamentation. To survey its genetic diversity and trace the history of domestication, we investigated a total of 4938 mitochondrial DNA (mtDNA) fragments including 2843 previously published and 2095 de novo units from 2044 domestic chickens and 51 red junglefowl (Gallus gallus). To obtain the highest possible level of molecular resolution, 50 representative samples were further selected for total mtDNA genome sequencing. A fine-gained mtDNA phylogeny was investigated by defining haplogroups A-I and W-Z. Common haplogroups A-G were shared by domestic chickens and red junglefowl. Rare haplogroups H-I and W-Z were specific to domestic chickens and red junglefowl, respectively. We re-evaluated the global mtDNA profiles of chickens. The geographic distribution for each of major haplogroups was examined. Our results revealed new complexities of history in chicken domestication because in the phylogeny lineages from the red junglefowl were mingled with those of the domestic chickens. Several local domestication events in South Asia, Southwest China and Southeast Asia were identified. The assessment of chicken mtDNA data also facilitated our understanding about the Austronesian settlement in the Pacific.