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Accumulating evidence indicates an association between the circadian clock and the aging process. However, it remains elusive whether the deregulation of circadian clock proteins underlies stem cell aging and whether they are targetable for the alleviation of aging-associated syndromes. Here, we identified a transcription factor-independent role of CLOCK, a core component of the molecular circadian clock machinery, in counteracting human mesenchymal stem cell (hMSC) decay. CLOCK expression was decreased during hMSC aging. In addition, CLOCK deficiency accelerated hMSC senescence, whereas the overexpression of CLOCK, even as a transcriptionally inactive form, rejuvenated physiologically and pathologically aged hMSCs. Mechanistic studies revealed that CLOCK formed complexes with nuclear lamina proteins and KAP1, thus maintaining heterochromatin architecture and stabilizing repetitive genomic sequences. Finally, gene therapy with lentiviral vectors encoding CLOCK promoted cartilage regeneration and attenuated age-related articular degeneration in mice. These findings demonstrate a noncanonical role of CLOCK in stabilizing heterochromatin, promoting tissue regeneration, and mitigating aging-associated chronic diseases.

Aging is a major risk factor for many diseases, especially in highly prevalent cardiopulmonary comorbidities and infectious diseases including Coronavirus Disease 2019 (COVID-19). Resolving cellular and molecular mechanisms associated with aging in higher mammals is therefore urgently needed. Here, we created young and old non-human primate single-nucleus/cell transcriptomic atlases of lung, heart and artery, the top tissues targeted by SARS-CoV-2. Analysis of cell type-specific aging-associated transcriptional changes revealed increased systemic inflammation and compromised virus defense as a hallmark of cardiopulmonary aging. With age, expression of the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) was increased in the pulmonary alveolar epithelial barrier, cardiomyocytes, and vascular endothelial cells. We found that interleukin 7 (IL7) accumulated in aged cardiopulmonary tissues and induced ACE2 expression in human vascular endothelial cells in an NF-κB-dependent manner. Furthermore, treatment with vitamin C blocked IL7-induced ACE2 expression. Altogether, our findings depict the first transcriptomic atlas of the aged primate cardiopulmonary system and provide vital insights into age-linked susceptibility to SARS-CoV-2, suggesting that geroprotective strategies may reduce COVID-19 severity in the elderly.

Aim Obesity is found to be associated with frailty. Body mass index (BMI) and waist circumference (WC) are the commonly used measures for obesity, the former is more closely related to general obesity and body weight; the latter can more accurately reflect abdominal obesity and is more closely associated with metabolic disorders. In this study, we intend to study the relationship between frailty, BMI and WC among older people. Methods Data were derived from the Beijing Longitudinal Study on Aging II Cohort, which included 6320 people 65 years or older from three urban districts in Beijing. A Frailty Index derived from 33 items was developed according to Rockwood’s cumulative deficits method. A Frailty Index ≥ 0.25 was used as the cut-off criteria. BMI was classified as underweight, normal, overweight, or obese (< 18.5, 18.5–< 24.0, 24.0–27.9, ≥ 28.0 kg/m 2 , respectively). High WC was defined as WC ≥ 85 cm in men and ≥ 80 cm in women. Results People with a larger BMI (≥ 28.0 kg/m 2 , 22.6%) or a larger WC (18.5%) were more likely to be frail. People with normal BMI and overweight people do not suffer from higher prevalence for frailty. In comparison with individuals with normal BMI (18.5–< 24.0 kg/m 2 ) and normal WC (< 85 cm in men, <80 cm in women), the risk of frailty was higher among individuals who have normal BMI and large WC (odds ratio 1.68; 95% CI 1.33–2.12), have overweight and large WC (odds ratio 1.58; 95% CI 1.23–1.96), or have obesity and large WC (odds ratio 2.28; 95% CI 1.79–2.89). In people with normal WC, only those who are underweight have a higher risk for frailty (odds ratio 1.65, 95% CI 1.08–2.52). In comparison with BMI, the relation of WC with the risk for frailty was much closer. Conclusions Abdominal obesity is more closely associated with incidence of frailty than general obesity in the elderly. Older adults with large waist circumference are more likely to be frail. Frailty in the elderly might be more closely related to metabolic disorders. WC might be a better measurement to detect frailty than BMI, given its relationship with metabolic disorders.

Our understanding of how aging affects the cellular and molecular components of the vasculature and contributes to cardiovascular diseases is still limited. Here we report a single-cell transcriptomic survey of aortas and coronary arteries in young and old cynomolgus monkeys. Our data define the molecular signatures of specialized arteries and identify eight markers discriminating aortic and coronary vasculatures. Gene network analyses characterize transcriptional landmarks that regulate vascular senility and position FOXO3A , a longevity-associated transcription factor, as a master regulator gene that is downregulated in six subtypes of monkey vascular cells during aging. Targeted inactivation of FOXO3A in human vascular endothelial cells recapitulates the major phenotypic defects observed in aged monkey arteries, verifying FOXO3A loss as a key driver for arterial endothelial aging. Our study provides a critical resource for understanding the principles underlying primate arterial aging and contributes important clues to future treatment of age-associated vascular disorders. Arterial degeneration, closely associated with cardiovascular diseases, is driven by aging-related vascular cell-specific transcriptomics changes. This study provides a single-cell transcriptomic atlas for senile aortic and coronary arteries and underscores FOXO3A -based the transcriptional network in vasoprotection during aging.

Alzheimer's disease (AD) is a common neurodegenerative disease in which the brain undergoes alterations for decades before symptoms become obvious. Subjective cognitive decline (SCD) have self-complain of persistent decline in cognitive function especially in memory but perform normally on standard neuropsychological tests. SCD with the presence of AD pathology is the transitional stage 2 of Alzheimer's continuum, earlier than the prodromal stage, mild cognitive impairment (MCI), which seems to be the best target to research AD. In this study, we aimed to detect the transformational patterns of the intrinsic brain activity as the disease burden got heavy. In this study, we enrolled 44 SCD, 55 amnestic MCI (aMCI), 47 AD dementia (d-AD) patients and 57 normal controls (NC) in total. A machine learning classification was utilized to detect identification accuracies between groups by using ALFF, fALFF, and fusing ALFF with fALFF features. Then, we measured the amplitude of the low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) levels in three frequency bands (classic: 0.01-0.1 Hz; slow-5: 0.01-0.027 Hz; and slow-4: 0.027-0.073 Hz) and compared alterations in patients with NC. In the machine learning verification, the identification accuracy of SCD, aMCI, d-AD from NC was higher when fused ALFF and fALFF features (76.44, 81.94, and 91.83%, respectively) than only using ALFF or fALFF features. Several brain regions showed significant differences in ALFF/fALFF within these bands among four groups: brain regions presented decreasing trend of values, including the Cingulum_Mid_R (aal), bilateral inferior cerebellum lobe, bilateral precuneus, and the Cingulum_Ant_R (aal); increasing trend of values were detected in the Hippocampus_L (aal), Frontal_Mid_Orb_R (aal), Frontal_Sup_R (aal) and Paracentral_Lobule_R (aal) as disease progressed. The normalized ALFF/fALFF values of these features were significantly correlated with the neuropsychological test scores. This study revealed gradual disturbances in intrinsic brain activity as the disease progressed: the normal objective performance in SCD may be dependent on compensation; as disease advanced, the cognitive function gradually impaired and decompensated in aMCI, severer in d-AD. Our results indicated that the ALFF and fALFF may help detect the underlying pathological mechanism in AD continuum. ClinicalTrials.gov, identifier NCT02353884 and NCT02225964.

Cellular senescence is a driver of various aging-associated disorders, including osteoarthritis. Here, we identified a critical role for Yes-associated protein (YAP), a major effector of Hippo signaling, in maintaining a younger state of human mesenchymal stem cells (hMSCs) and ameliorating osteoarthritis in mice. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated protein 9 nuclease (Cas9)-mediated knockout (KO) of YAP in hMSCs resulted in premature cellular senescence. Mechanistically, YAP cooperated with TEA domain transcriptional factor (TEAD) to activate the expression of forkhead box D1 (FOXD1), a geroprotective protein. YAP deficiency led to the down-regulation of FOXD1. In turn, overexpression of YAP or FOXD1 rejuvenated aged hMSCs. Moreover, intra-articular administration of lentiviral vector encoding YAP or FOXD1 attenuated the development of osteoarthritis in mice. Collectively, our findings reveal YAP-FOXD1, a novel aging-associated regulatory axis, as a potential target for gene therapy to alleviate osteoarthritis.

Iron deposition is present in main lesion areas in the brains of patients with Parkinson’s disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis . We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD.

DiGeorge syndrome critical region 8 (DGCR8) is a critical component of the canonical microprocessor complex for microRNA biogenesis. However, the non-canonical functions of DGCR8 have not been studied. Here, we demonstrate that DGCR8 plays an important role in maintaining heterochromatin organization and attenuating aging. An N-terminal-truncated version of DGCR8 (DR8 dex2 ) accelerated senescence in human mesenchymal stem cells (hMSCs) independent of its microRNA-processing activity. Further studies revealed that DGCR8 maintained heterochromatin organization by interacting with the nuclear envelope protein Lamin B1, and heterochromatin-associated proteins, KAP1 and HP1γ. Overexpression of any of these proteins, including DGCR8, reversed premature senescent phenotypes in DR8 dex2 hMSCs. Finally, DGCR8 was downregulated in pathologically and naturally aged hMSCs, whereas DGCR8 overexpression alleviated hMSC aging and mouse osteoarthritis. Taken together, these analyses uncovered a novel, microRNA processing-independent role in maintaining heterochromatin organization and attenuating senescence by DGCR8, thus representing a new therapeutic target for alleviating human aging-related disorders. DGCR8 is a component of the canonical microprocessor complex for microRNA biogenesis. Here the authors implicate DGCR8 in heterochromatin maintenance and aging attenuation independent of its miRNA-processing activity through Lamin B1, KAP1 and HP1 interaction. DGCR8 overexpression can alleviate aging and senescence

The longitudinal relationship between fatigue and physical deterioration is least explored. The aim of the study was to investigate the physical performance transitions and the relationship with adverse outcomes over 3-years in older people with or without fatigue. This 3-year longitudinal study included 456 community-dwelling older adults (mean age: 73.5 ± 7.5 years; female 43.0%). Physical performance was assessed using the Short Physical Performance Battery (SPPB). Fatigue was assessed by a single-item question “Have you felt tired or fatigued on at least 3 or 4 days each week?” At follow-up, both groups showed a trend towards lower physical performance levels, with the fatigue group exhibiting a significantly more pronounced decline. After adjusting for covariates, new-onset sarcopenia(OR = 3.08, 95%CI = 2.18–5.45) and malnutrition(OR = 2.70, 95%CI = 1.38–5.57) were the significant adverse events associated with physical performance deterioration in individuals with fatigue at 3-year follow-up. While for non-fatigue older adults, cognitive impairment (OR = 1.81,95%CI = 1.52–3.84) and sarcopenia(OR = 1.83, 95%CI = 1.50–5.33) were the significant adverse events associated with physical performance deterioration. The characteristics of older individuals with and without fatigue are distinct while considering longitudinal physical performance transitions. Fatigue is a significant risk factor associated with geriatric syndromes such as sarcopenia and malnutrition in individuals who have poor physical performance. Clinical trial number: ChiCTR2100051397.

Multimorbidity is common in older hospitalized adults. To date, however, few studies have addressed multimorbidity in the older population of Chinese inpatients. We aimed to investigate the multimorbidity rate and associated risk factors in older adult inpatients in China. This study was conducted in the medical wards of a tertiary-care hospital from. The patients were recruited aged between 60 to 101 (74.14±8.46) years. Data were obtained from the China Comprehensive Geriatric Assessment Study, conducted in 2011–2012 in China. A total of 4,633 inpatients older than 60 years was recruited from 12 hospitals in 7 cities throughout China. The prevalence of comorbidity, distribution of common chronic diseases, and the associated risk factors were studied. A total of 4,348 people aged 60 to 101 (74.14±8.46) years completed questionnaires. The average frequency of multimorbidity was 69.3% (95% CI, 67.9% to 70.6%). The prevalence of multimorbidity increased with age and was higher in men (71.6%; 95% CI, 69.9% to 73.3%) than in women (65.3%, 95% CI 63.0% to 67.6%), and higher in the northern region (71.7%, 95% CI 69.9% to 73.5%) than in the southern region (66.0%; 95% CI, 63.8% to 68.1%). The most frequent chronic diseases were hypertension, coronary heart disease, diabetes, cataract, and stroke. Area (OR=0.556; 95% CI, 0.465 to 0.666), region (OR=0.834; 95% CI, 0.723 to 0.962), body mass index (BMI) (OR=1.124; 95% CI, 1.017 to 1.242), and impairment of activities of daily living (OR=0.911; 95% CI, 0.855 to 0.970) were independent factors associated with multimorbidity. Multimorbidity is common in older Chinese inpatients with a national prevalence of 69.3% that increases in line with age. Age, region, area, BMI, and daily activities were independent factors significantly associated with multimorbidity in older inpatients. Clinicians should therefore focus more attention on multimorbidity.