bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–04–03
twenty-one papers selected by
Ayesh Seneviratne, University of Toronto
  1. Advances in understanding the molecular basis of clonal hematopoiesis.
  2. PTIP governs NAD+ metabolism by regulating CD38 expression to drive macrophage inflammation.
  3. Oxysterols are potential physiological regulators of ageing.
  4. Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization.
  5. Circulating biomarkers of inflammaging as potential predictors of COVID-19 severe outcomes.
  6. Multimorbidity patterns and their relationships with incident disability and frailty among older adults in Taiwan: A 16-year, population-based cohort study.
  7. Will Omicron finally overpower China's COVID defences?
  8. Cell senescence, rapamycin and hyperfunction theory of aging.
  9. Proteinuria as a Nascent Predictor of Frailty Among People With Metabolic Syndrome: A Retrospective Observational Study.
  10. Differential Effects of the Soluble Fiber Inulin in Reducing Adiposity and Altering Gut Microbiome in Aging Mice.
  11. Killifish switch towards mammalian-like regeneration upon aging.
  12. Targeted clearance of p21- but not p16-positive senescent cells prevents radiation-induced osteoporosis and increased marrow adiposity.
  13. Anabolic Function Downstream of TOR Controls Trade-offs Between Longevity and Reproduction at the Level of Specific Tissues in C. elegans.
  14. Predicting Falls in Long-term Care Facilities: Machine Learning Study.
  15. Hallmarks of aging-based dual-purpose disease and age-associated targets predicted using PandaOmics AI-powered discovery engine.
  16. [Venetoclax: A New Hope for Elderly Patients with Acute Myeloid Leukemia].
  17. B cells regulate hematopoietic stem cells via cholinergic signaling.
  18. Promoting Lifespan Health and Well-Being Through the Autism Intervention Research Network.
  19. Age-dependent formation of TMEM106B amyloid filaments in human brains.
  20. Editorial: Pharmacogenomics: From Bench to Bedside and Back Again.
  21. An objective metric of individual health and aging for population surveys.
  1. Trends Mol Med. 2022 Mar 25. pii: S1471-4914(22)00054-5. [Epub ahead of print]
    Advances in understanding the molecular basis of clonal hematopoiesis.
    David A Alagpulinsa, Mabel P Toribio, Iad Alhallak, Robert J Shmookler Reis.
      Hematopoietic stem cells (HSCs) are polyfunctional, regenerating all blood cells via hematopoiesis throughout life. Clonal hematopoiesis (CH) is said to occur when a substantial proportion of mature blood cells is derived from a single dominant HSC lineage, usually because these HSCs have somatic mutations that confer a fitness and expansion advantage. CH strongly associates with aging and enrichment in some diseases irrespective of age, emerging as an independent causal risk factor for hematologic malignancies, cardiovascular disease, adverse disease outcomes, and all-cause mortality. Defining the molecular mechanisms underlying CH will thus provide a framework to develop interventions for healthy aging and disease treatment. Here, we review the most recent advances in understanding the molecular basis of CH in health and disease.
    Keywords:  DNA damage; aging; cardiovascular disease; clonal hematopoiesis; hematopoietic stem cells; inflammation; leukemia; mutations
    DOI:  https://doi.org/10.1016/j.molmed.2022.03.002
  2. Cell Rep. 2022 Mar 29. pii: S2211-1247(22)00351-5. [Epub ahead of print]38(13): 110603
    PTIP governs NAD+ metabolism by regulating CD38 expression to drive macrophage inflammation.
    Qifan Wang, Jin Hu, Guoqiang Han, Peipei Wang, Sha Li, Jiwei Chang, Kexin Gao, Rong Yin, Yashu Li, Tong Zhang, Jihua Chai, Zhuying Gao, Tiantian Zhang, Ying Cheng, Chengli Guo, Jing Wang, Weidong Liu, Manman Cui, Yu Xu, Jinxuan Hou, Quan-Fei Zhu, Yu-Qi Feng, Haojian Zhang.
      NAD+ metabolism is involved in many biological processes. However, the underlying mechanism of how NAD+ metabolism is regulated remains elusive. Here, we find that PTIP governs NAD+ metabolism in macrophages by regulating CD38 expression and is required for macrophage inflammation. Through integrating histone modifications with NAD+ metabolic gene expression profiling, we identify PTIP as a key factor in regulating CD38 expression, the primary NAD+-consuming enzyme in macrophages. Interestingly, we find that PTIP deletion impairs the proinflammatory response of primary murine and human macrophages, promotes their metabolic switch from glycolysis to oxidative phosphorylation, and alters NAD+ metabolism via downregulating CD38 expression. Mechanistically, an intronic enhancer of CD38 is identified. PTIP regulates CD38 expression by cooperating with acetyltransferase p300 in establishing the CD38 active enhancer with enriched H3K27ac. Overall, our findings reveal a critical role for PTIP in fine-tuning the inflammatory responses of macrophages via regulating NAD+ metabolism.
    Keywords:  CD38; CP: Immunology; CP: Metabolism; NAD(+); PTIP; inflammation; macrophage
    DOI:  https://doi.org/10.1016/j.celrep.2022.110603
  3. Ageing Res Rev. 2022 Mar 26. pii: S1568-1637(22)00057-5. [Epub ahead of print] 101615
    Oxysterols are potential physiological regulators of ageing.
    Philippe de Medina, Sandrine Silvente-Poirot, Marc Poirot.
      Delaying and even reversing ageing is a major public health challenge with a tremendous potential to postpone a plethora of diseases including cancer, metabolic syndromes and neurodegenerative disorders. A better understanding of ageing as well as the development of innovative anti-ageing strategies are therefore an increasingly important field of research. Several biological processes including inflammation, proteostasis, epigenetic, oxidative stress, stem cell exhaustion, senescence and stress adaptive response have been reported for their key role in ageing. In this review, we describe the relationships that have been established between cholesterol homeostasis, in particular at the level of oxysterols, and ageing. Initially considered as harmful pro-inflammatory and cytotoxic metabolites, oxysterols are currently emerging as an expanding family of fine regulators of various biological processes involved in ageing. Indeed, depending of their chemical structure and their concentration, oxysterols exhibit deleterious or beneficial effects on inflammation, oxidative stress and cell survival. In addition, stem cell differentiation, epigenetics, cellular senescence and proteostasis are also modulated by oxysterols. Altogether, these data support the fact that ageing is influenced by an oxysterol profile. Further studies are thus required to explore more deeply the impact of the "oxysterome" on ageing and therefore this cholesterol metabolic pathway constitutes a promising target for future anti-ageing interventions.
    Keywords:  ageing; cholesterol homeostasis; metabolism; oxysterome; stress adaptive response
    DOI:  https://doi.org/10.1016/j.arr.2022.101615
  4. Aging Cell. 2022 Mar 27. e13596
    Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization.
    Ameya S Kulkarni, Sandra Aleksic, David M Berger, Felipe Sierra, George A Kuchel, Nir Barzilai.
      Common chronic diseases represent the greatest driver of rising healthcare costs, as well as declining function, independence, and quality of life. Geroscience-guided approaches seek to delay the onset and progression of multiple chronic conditions by targeting fundamental biological pathways of aging. This approach is more likely to improve overall health and function in old age than treating individual diseases, by addressing aging the largest and mostly ignored risk factor for the leading causes of morbidity in older adults. Nevertheless, challenges in repurposing existing and moving newly discovered interventions from the bench to clinical care have impeded the progress of this potentially transformational paradigm shift. In this article, we propose the creation of a standardized process for evaluating FDA-approved medications for their geroscience potential. Criteria for systematically evaluating the existing literature that spans from animal models to human studies will permit the prioritization of efforts and financial investments for translating geroscience and allow immediate progress on the design of the next Targeting Aging with MEtformin (TAME)-like study involving such candidate gerotherapeutics.
    Keywords:  aging; clinical trials; drug repurposing; geroscience; preclinical studies
    DOI:  https://doi.org/10.1111/acel.13596
  5. Mech Ageing Dev. 2022 Mar 25. pii: S0047-6374(22)00049-5. [Epub ahead of print]204 111667
    Circulating biomarkers of inflammaging as potential predictors of COVID-19 severe outcomes.
    Jacopo Sabbatinelli, Giulia Matacchione, Angelica Giuliani, Deborah Ramini, Maria Rita Rippo, Antonio Domenico Procopio, Massimiliano Bonafè, Fabiola Olivieri.
      The COVID-19 pandemic caused by SARS-CoV-2 infection has been of unprecedented clinical and socio-economic worldwide relevance. The case fatality rate for COVID-19 grows exponentially with age and the presence of comorbidities. In the older patients, COVID-19 manifests predominantly as a systemic disease associated with immunological, inflammatory, and procoagulant responses. Timely diagnosis and risk stratification are crucial steps to define appropriate therapies and reduce mortality, especially in the older patients. Chronically and systemically activated innate immune responses and impaired antiviral responses have been recognized as the results of a progressive remodeling of the immune system during aging, which can be described by the words 'immunosenescence' and 'inflammaging'. These age-related features of the immune system were highlighted in patients affected by COVID-19 with the poorest clinical outcomes, suggesting that the mechanisms underpinning immunosenescence and inflammaging could be relevant for COVID-19 pathogenesis and progression. Increasing evidence suggests that senescent myeloid and endothelial cells are characterized by the acquisition of a senescence-associated pro-inflammatory phenotype (SASP), which is considered as the main culprit of both immunosenescence and inflammaging. Here, we reviewed this evidence and highlighted several circulating biomarkers of inflammaging that could provide additional prognostic information to stratify COVID-19 patients based on the risk of severe outcomes.
    Keywords:  Biomarkers; COVID-19; Inflammaging; Neutrophils; SARS-CoV-2
    DOI:  https://doi.org/10.1016/j.mad.2022.111667
  6. Arch Gerontol Geriatr. 2022 Mar 20. pii: S0167-4943(22)00069-3. [Epub ahead of print]101 104688
    Multimorbidity patterns and their relationships with incident disability and frailty among older adults in Taiwan: A 16-year, population-based cohort study.
    Hsin-En Ho, Chih-Jung Yeh, James Cheng-Chung Wei, Wei-Min Chu, Meng-Chih Lee.
       BACKGROUND: Multimorbidity has negative impacts on the health outcomes of older adults. Previous research has discovered different patterns of multimorbidity. However, evidence is scarce for associations between multimorbidity patterns and disability/frailty, especially evidence from longitudinal studies. This study aimed to explore the relationship between multimorbidity patterns and disability/frailty among older adults in Taiwan.
    METHODS: This population-based cohort study used data from the Taiwan Longitudinal Study on Aging. It included 2,194 older adults (age >50 years) who were followed from 1996 to 2011. The participants' multimorbidity patterns in 1996 were determined by latent class analysis; their incident disability and frailty were ascertained in 2011. Multivariate logistic regression was used to analyze the relationship between multimorbidity patterns and disability/frailty.
    RESULTS: In 1996, the participants' average age was 62 years. Four multimorbidity patterns were discovered through latent class analysis, as follows: (1) Cardiometabolic group (n = 222), (2) Arthritis-cataract group (n = 112), (3) Multimorbidity group (n = 189), and (4) Relatively healthy group (n = 1671). After adjusting for age, sex, social participation, alcohol consumption, self-rated health, admission in the past year, and depression, participants in the Cardiometabolic group had a greater risk of incident disability (odds ratio: 1.78; 95% confidence interval: 1.26-2.52), compared with the Relatively healthy group. No statistically significant relationships were found between multimorbidity patterns and frailty. Subgroup analysis showed that females in the Cardiometabolic and Multimorbidity groups had greater risks of developing disability.
    CONCLUSION: This 16-year, population-based cohort study showed that distinct multimorbidity patterns among older adults in Taiwan were associated with incident disability during later life but were not related to frailty.
    Keywords:  Disability; Frailty; Multimorbidity patterns; Older adults
    DOI:  https://doi.org/10.1016/j.archger.2022.104688
  7. Nature. 2022 Mar 28.
    Will Omicron finally overpower China's COVID defences?
    Dyani Lewis.
      
    Keywords:  Public health; SARS-CoV-2; Vaccines
    DOI:  https://doi.org/10.1038/d41586-022-00884-z
  8. Cell Cycle. 2022 Mar 31. 1-12
    Cell senescence, rapamycin and hyperfunction theory of aging.
    Mikhail V Blagosklonny.
      A hallmark of cellular senescence is proliferation-like activity of growth-promoting pathways (such as mTOR and MAPK) in non-proliferating cells. When the cell cycle is arrested, these pathways convert arrest to senescence (geroconversion), rendering cells hypertrophic, beta-Gal-positive and hyperfunctional. The senescence-associated secretory phenotype (SASP) is one of the numerous hyperfunctions. Figuratively, geroconversion is a continuation of growth in non-proliferating cells. Rapamycin, a reversible inhibitor of growth, slows down mTOR-driven geroconversion. Developed two decades ago, this model had accurately predicted that rapamycin must extend life span of animals. However, the notion that senescent cells directly cause organismal aging is oversimplified. Senescent cells contribute to organismal aging but are not strictly required. Cell senescence and organismal aging can be linked indirectly via the same underlying cause, namely hyperfunctional signaling pathways such as mTOR.
    Keywords:  Senescence; geroconversion; geroscience; gerostatics; healthspan; rapalogs; sirolimus
    DOI:  https://doi.org/10.1080/15384101.2022.2054636
  9. Front Public Health. 2022 ;10 847533
    Proteinuria as a Nascent Predictor of Frailty Among People With Metabolic Syndrome: A Retrospective Observational Study.
    Pi-Kai Chang, Yuan-Ping Chao, Li-Wei Wu.
      Frailty is a commonly occurring geriatric condition that increases the risk of adverse health outcomes. The factors and predictors behind frailty are not yet well understood. A better understanding of these factors can enable prevention of frailty in elderly patients. The objective of this study was to determine the association between proteinuria and frailty in US individuals with metabolic syndrome (MetS). Data from the National Health and Nutrition Examination Survey III (NHANES III, 1988-1994) conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention. This is a cross-sectional study, and proteinuria and frailty were measured only once at enrollment. The study included 2,272 participants with MetS aged 40-90 years from the NHANES III. The participants underwent assessments to evaluate frailty and frailty components (low body weight, weakness, exhaustion, low physical activity, and slow walking). Proteinuria was represented as albumin-to-creatinine ratio (ACR) (mg/g) and divided into tertiles: T1-normal range (ACR <30 mg/g), T2-microalbuminuria (ACR 30-299 mg/g), and T3-macroalbuminuria (ACR ≥ 300 mg/g). We applied multiple logistic regression to determine the odds ratios (ORs) of frailty for T2 vs. T1 and T3 vs. T1 in both sexes. In the adjusted analysis for male participants, the ORs of frailty for T2 and T3 vs. T1 were 3.106 (95% confidence interval [CI] = 1.078-8.948, P = 0.036) and 14.428 (95% CI = 4.231-49.193, P < 0.001), respectively. For female participants, the ORs of frailty for T2 and T3 vs. T1 were 1.811 (95% CI = 1.071-3.063, P = 0.027) and 2.926 (95% CI = 1.202-7.124, P = 0.018), respectively. The positive association between T2 and T3 vs. T1, and frailty were statistically significant. The trends of higher likelihood of every frailty component were also statistically significant across increasing tertiles of proteinuria after multiple levels of adjustment for covariates (P < 0.05). Increased proteinuria levels were positively associated with frailty and each frailty component. Proteinuria might be a useful maker for frailty in individuals with MetS.
    Keywords:  National Health and Nutrition Examination Survey; albumin to creatinine ratio; fraility; metabolic sybdrome; proteinuria
    DOI:  https://doi.org/10.3389/fpubh.2022.847533
  10. J Nutr Biochem. 2022 Mar 25. pii: S0955-2863(22)00070-5. [Epub ahead of print] 108999
    Differential Effects of the Soluble Fiber Inulin in Reducing Adiposity and Altering Gut Microbiome in Aging Mice.
    Sai Deepak Venkata Muthyala, Smriti Shankar, Cory Klemashevich, John C Blazier, Andrew Hillhouse, Chia-Shan Wu.
      Inulin, a soluble dietary fiber, is thought to exert multiple beneficiary effects through promoting growth of bacteria that metabolize the fiber to short-chain fatty acids (SCFAs); however, the effect and efficacy of inulin in aging subjects is unknown. This study aims to systematically evaluate the capacity of SCFAs production and host response in mice of different ages. Male C57BL/6J mice across young (5 months), middle (11 months) and old (26 months) age were subjected to a control diet for two weeks, followed by 6 weeks of inulin-containing diet. Inulin-induced increase in fecal butyric acid levels was most prominent in middle-age group compared to other age groups. In addition, inulin-induced increase in fecal propionic acids showed age-dependent decline. Interestingly, the SCFA-producing Roseburia was most abundantly and persistently increased in the middle-age group. Furthermore, inulin intake significantly reduced Firmicutes to Bacteroidetes ratio, and several dysbiotic bacteria associated with pro-inflammatory state. Concomitantly, circulating levels of CXCL1, a chemoattractant for neutrophils, was reduced by inulin intake. Inulin decreased fat mass in all age groups, with middle-aged mice being most responsive to fat-reducing effects of inulin. Moreover, inulin significantly increased energy expenditure and voluntary wheel running in middle-aged mice, but not in old mice. Overall, our data suggest that the efficacy of inulin in altering the microbiome and SCFA production, and the subsequent metabolic response was diminished in old mice, and highlight the importance of including age as a variable in studies determining host-microbe response to diets.
    Keywords:  Short-chain fatty acids; aging; dietary fiber; gut microbiome; inulin; metabolism
    DOI:  https://doi.org/10.1016/j.jnutbio.2022.108999
  11. Aging (Albany NY). 2022 Mar 31. undefined(undefined):
    Killifish switch towards mammalian-like regeneration upon aging.
    Sophie Vanhunsel, Steven Bergmans, Lieve Moons.
      
    Keywords:  African turquoise killifish; aging hallmarks; axonal regeneration; central nervous system; short lifespan
    DOI:  https://doi.org/10.18632/aging.203995
  12. Aging Cell. 2022 Apr 01. e13602
    Targeted clearance of p21- but not p16-positive senescent cells prevents radiation-induced osteoporosis and increased marrow adiposity.
    Abhishek Chandra, Anthony B Lagnado, Joshua N Farr, Madison Doolittle, Tamara Tchkonia, James L Kirkland, Nathan K LeBrasseur, Paul D Robbins, Laura J Niedernhofer, Yuji Ikeno, João F Passos, David G Monroe, Robert J Pignolo, Sundeep Khosla.
      Cellular senescence, which is a major cause of tissue dysfunction with aging and multiple other conditions, is known to be triggered by p16Ink4a or p21Cip1 , but the relative contributions of each pathway toward inducing senescence are unclear. Here, we directly addressed this issue by first developing and validating a p21-ATTAC mouse with the p21Cip1 promoter driving a "suicide" transgene encoding an inducible caspase-8 which, upon induction, selectively kills p21Cip1 -expressing senescent cells. Next, we used the p21-ATTAC mouse and the established p16-INK-ATTAC mouse to directly compare the contributions of p21Cip1 versus p16Ink4a in driving cellular senescence in a condition where a tissue phenotype (bone loss and increased marrow adiposity) is clearly driven by cellular senescence-specifically, radiation-induced osteoporosis. Using RNA in situ hybridization, we confirmed the reduction in radiation-induced p21Cip1 - or p16Ink4a -driven transcripts following senescent cell clearance in both models. However, only clearance of p21Cip1 +, but not p16Ink4a +, senescent cells prevented both radiation-induced osteoporosis and increased marrow adiposity. Reduction in senescent cells with dysfunctional telomeres following clearance of p21Cip1 +, but not p16Ink4a +, senescent cells also reduced several of the radiation-induced pro-inflammatory senescence-associated secretory phenotype factors. Thus, by directly comparing senescent cell clearance using two parallel genetic models, we demonstrate that radiation-induced osteoporosis is driven predominantly by p21Cip1 - rather than p16Ink4a -mediated cellular senescence. Further, this approach can be used to dissect the contributions of these pathways in other senescence-associated conditions, including aging across tissues.
    Keywords:  bone; radiation; senescence
    DOI:  https://doi.org/10.1111/acel.13602
  13. Front Aging. 2021 Sep;pii: 725068. [Epub ahead of print]2
    Anabolic Function Downstream of TOR Controls Trade-offs Between Longevity and Reproduction at the Level of Specific Tissues in C. elegans.
    Amber C Howard, Dilawar Mir, Santina Snow, Jordan Horrocks, Hussein Sayed, Zhengxin Ma, Aric N Rogers.
      As the most energetically expensive cellular process, translation must be finely tuned to environmental conditions. Dietary restriction attenuates signaling through the nutrient sensing mTOR pathway, which reduces translation and redirects resources to preserve the soma. These responses are associated with increased lifespan but also anabolic impairment, phenotypes also observed when translation is genetically suppressed. Here, we restricted translation downstream of mTOR separately in major tissues in C. elegans to better understand their roles in systemic adaptation and whether consequences to anabolic impairment were separable from positive effects on lifespan. Lowering translation in neurons, hypodermis, or germline tissue led to increased lifespan under well-fed conditions and improved survival upon withdrawal of food, indicating that these are key tissues coordinating enhanced survival when protein synthesis is reduced. Surprisingly, lowering translation in body muscle during development shortened lifespan while accelerating and increasing reproduction, a reversal of phenotypic trade-offs associated with systemic translation suppression. Suppressing mTORC1 selectively in body muscle also increased reproduction while slowing motility during development. In nature, this may be indicative of reduced energy expenditure related to foraging, acting as a "GO!" signal for reproduction. Together, results indicate that low translation in different tissues helps direct distinct systemic adaptations and suggest that unknown endocrine signals mediate these responses. Furthermore, mTOR or translation inhibitory therapeutics that target specific tissues may achieve desired interventions to aging without loss of whole-body anabolism.
    Keywords:  adaptive response; aging; cell non-autonomous; lifespan; mRNA translation; optimal foraging theory; reproduction; trade-offs
    DOI:  https://doi.org/10.3389/fragi.2021.725068
  14. JMIR Aging. 2022 Apr 01. 5(2): e35373
    Predicting Falls in Long-term Care Facilities: Machine Learning Study.
    Rahul Thapa, Anurag Garikipati, Sepideh Shokouhi, Myrna Hurtado, Gina Barnes, Jana Hoffman, Jacob Calvert, Lynne Katzmann, Qingqing Mao, Ritankar Das.
       BACKGROUND: Short-term fall prediction models that use electronic health records (EHRs) may enable the implementation of dynamic care practices that specifically address changes in individualized fall risk within senior care facilities.
    OBJECTIVE: The aim of this study is to implement machine learning (ML) algorithms that use EHR data to predict a 3-month fall risk in residents from a variety of senior care facilities providing different levels of care.
    METHODS: This retrospective study obtained EHR data (2007-2021) from Juniper Communities' proprietary database of 2785 individuals primarily residing in skilled nursing facilities, independent living facilities, and assisted living facilities across the United States. We assessed the performance of 3 ML-based fall prediction models and the Juniper Communities' fall risk assessment. Additional analyses were conducted to examine how changes in the input features, training data sets, and prediction windows affected the performance of these models.
    RESULTS: The Extreme Gradient Boosting model exhibited the highest performance, with an area under the receiver operating characteristic curve of 0.846 (95% CI 0.794-0.894), specificity of 0.848, diagnostic odds ratio of 13.40, and sensitivity of 0.706, while achieving the best trade-off in balancing true positive and negative rates. The number of active medications was the most significant feature associated with fall risk, followed by a resident's number of active diseases and several variables associated with vital signs, including diastolic blood pressure and changes in weight and respiratory rates. The combination of vital signs with traditional risk factors as input features achieved higher prediction accuracy than using either group of features alone.
    CONCLUSIONS: This study shows that the Extreme Gradient Boosting technique can use a large number of features from EHR data to make short-term fall predictions with a better performance than that of conventional fall risk assessments and other ML models. The integration of routinely collected EHR data, particularly vital signs, into fall prediction models may generate more accurate fall risk surveillance than models without vital signs. Our data support the use of ML models for dynamic, cost-effective, and automated fall predictions in different types of senior care facilities.
    Keywords:  aging; assisted living facilities; blood pressure; elderly care; elderly population; fall prediction; independent living facilities; machine learning; older adult; skilled nursing facilities; vital signs
    DOI:  https://doi.org/10.2196/35373
  15. Aging (Albany NY). 2022 Mar 29. 14(undefined):
    Hallmarks of aging-based dual-purpose disease and age-associated targets predicted using PandaOmics AI-powered discovery engine.
    Frank W Pun, Geoffrey Ho Duen Leung, Hoi Wing Leung, Bonnie Hei Man Liu, Xi Long, Ivan V Ozerov, Ju Wang, Feng Ren, Alexander Aliper, Evgeny Izumchenko, Alexey Moskalev, João Pedro de Magalhães, Alex Zhavoronkov.
      Aging biology is a promising and burgeoning research area that can yield dual-purpose pathways and protein targets that may impact multiple diseases, while retarding or possibly even reversing age-associated processes. One widely used approach to classify a multiplicity of mechanisms driving the aging process is the hallmarks of aging. In addition to the classic nine hallmarks of aging, processes such as extracellular matrix stiffness, chronic inflammation and activation of retrotransposons are also often considered, given their strong association with aging. In this study, we used a variety of target identification and prioritization techniques offered by the AI-powered PandaOmics platform, to propose a list of promising novel aging-associated targets that may be used for drug discovery. We also propose a list of more classical targets that may be used for drug repurposing within each hallmark of aging. Most of the top targets generated by this comprehensive analysis play a role in inflammation and extracellular matrix stiffness, highlighting the relevance of these processes as therapeutic targets in aging and age-related diseases. Overall, our study reveals both high confidence and novel targets associated with multiple hallmarks of aging and demonstrates application of the PandaOmics platform to target discovery across multiple disease areas.
    Keywords:  artificial intelligence; deep learning; drug discovery; multi-omics; target identification
    DOI:  https://doi.org/10.18632/aging.203960
  16. Acta Med Port. 2022 Mar 29.
    [Venetoclax: A New Hope for Elderly Patients with Acute Myeloid Leukemia].
    Bárbara Marques, Carolina Afonso, Emília Cortesão.
      Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by clonal proliferation, with increased incidence with advancing age. AML with myelodysplasia-related changes (AML-MRC) represents an AML subtype with a poor prognosis and challenging treatment, particularly in elderly patients. We report the case of a 77-year-old patient diagnosed with high-risk AML-MRC, ineligible for intensive chemotherapy, with frequent need of transfusion of red cell concentrates. The authors present, to the best of their knowledge, the first patient in Portugal with AML-MRC treated with an hypomethylating agent, azacytidine, and a BCL2 inhibitor (venetoclax), and that association was essential in the treatment and overall survival, which was much higher than expected.
    Keywords:  Aged; Bridged Bicyclo Compounds, Heterocyclic; Leukemia, Myeloid, Acute/drug therapy
    DOI:  https://doi.org/10.20344/amp.17770
  17. Nat Immunol. 2022 Mar 28.
    B cells regulate hematopoietic stem cells via cholinergic signaling.
    Sweta B Patel, Eric M Pietras.
      
    DOI:  https://doi.org/10.1038/s41590-022-01172-8
  18. Pediatrics. 2022 Apr 01. pii: e2020049437B. [Epub ahead of print]149(Suppl 4):
    Promoting Lifespan Health and Well-Being Through the Autism Intervention Research Network.
    Alice A Kuo.
      
    DOI:  https://doi.org/10.1542/peds.2020-049437B
  19. Nature. 2022 Mar 28.
    Age-dependent formation of TMEM106B amyloid filaments in human brains.
    Manuel Schweighauser, Diana Arseni, Mehtap Bacioglu, Melissa Huang, Sofia Lövestam, Yang Shi, Yang Yang, Wenjuan Zhang, Abhay Kotecha, Holly J Garringer, Ruben Vidal, Grace I Hallinan, Kathy L Newell, Airi Tarutani, Shigeo Murayama, Masayuki Miyazaki, Yuko Saito, Mari Yoshida, Kazuko Hasegawa, Tammaryn Lashley, Tamas Revesz, Gabor G Kovacs, John van Swieten, Masaki Takao, Masato Hasegawa, Bernardino Ghetti, Maria Grazia Spillantini, Benjamin Ryskeldi-Falcon, Alexey G Murzin, Michel Goedert, Sjors H W Scheres.
      Many age-dependent neurodegenerative diseases, like Alzheimer's and Parkinson's, are characterised by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β (Aβ), α-synuclein and TDP-43 are the most common1,2. Here, we used electron cryo-microscopy (cryo-EM) structure determination to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in human brains. We determined the cryo-EM structures of TMEM106B filaments from a number of brain regions of 22 individuals with abundant amyloid deposits, including sporadic and inherited tauopathies, Aβ-amyloidoses, synucleinopathies and TDP-43 proteinopathies, as well as from the frontal cortex of 3 neurologically normal individuals with no or only few amyloid deposits. We observed three TMEM106B folds, with no clear relationships between folds and diseases. TMEM106B filaments correlated with the presence of a 29 kDa sarkosyl-insoluble fragment and globular cytoplasmic inclusions, as detected by an antibody specific for the C-terminal region of TMEM106B. The identification of TMEM106B filaments in the brains of older, but not younger, neurologically normal individuals indicates that they form in an age-dependent manner.
    DOI:  https://doi.org/10.1038/s41586-022-04650-z
  20. Front Genet. 2022 ;13 878191
    Editorial: Pharmacogenomics: From Bench to Bedside and Back Again.
    Jeffrey A Shaman, Chad A Bousman, Christina Mitropoulou, Sandosh Padmanabhan.
      
    Keywords:  HLA antigens; adverse drug reaction; clinical implementation; clinical practice; cytochrome P450; incidental findings; pharmacogenomics
    DOI:  https://doi.org/10.3389/fgene.2022.878191
  21. Popul Health Metr. 2022 Mar 31. 20(1): 11
    An objective metric of individual health and aging for population surveys.
    Qing Li, Véronique Legault, Vincent-Daniel Girard, Luigi Ferrucci, Linda P Fried, Alan A Cohen.
       BACKGROUND: We have previously developed and validated a biomarker-based metric of overall health status using Mahalanobis distance (DM) to measure how far from the norm of a reference population (RP) an individual's biomarker profile is. DM is not particularly sensitive to the choice of biomarkers; however, this makes comparison across studies difficult. Here we aimed to identify and validate a standard, optimized version of DM that would be highly stable across populations, while using fewer and more commonly measured biomarkers.
    METHODS: Using three datasets (the Baltimore Longitudinal Study of Aging, Invecchiare in Chianti and the National Health and Nutrition Examination Survey), we selected the most stable sets of biomarkers in all three populations, notably when interchanging RPs across populations. We performed regression models, using a fourth dataset (the Women's Health and Aging Study), to compare the new DM sets to other well-known metrics [allostatic load (AL) and self-assessed health (SAH)] in their association with diverse health outcomes: mortality, frailty, cardiovascular disease (CVD), diabetes, and comorbidity number.
    RESULTS: A nine- (DM9) and a seventeen-biomarker set (DM17) were identified as highly stable regardless of the chosen RP (e.g.: mean correlation among versions generated by interchanging RPs across dataset of r = 0.94 for both DM9 and DM17). In general, DM17 and DM9 were both competitive compared with AL and SAH in predicting aging correlates, with some exceptions for DM9. For example, DM9, DM17, AL, and SAH all predicted mortality to a similar extent (ranges of hazard ratios of 1.15-1.30, 1.21-1.36, 1.17-1.38, and 1.17-1.49, respectively). On the other hand, DM9 predicted CVD less well than DM17 (ranges of odds ratios of 0.97-1.08, 1.07-1.85, respectively).
    CONCLUSIONS: The metrics we propose here are easy to measure with data that are already available in a wide array of panel, cohort, and clinical studies. The standardized versions here lose a small amount of predictive power compared to more complete versions, but are nonetheless competitive with existing metrics of overall health. DM17 performs slightly better than DM9 and should be preferred in most cases, but DM9 may still be used when a more limited number of biomarkers is available.
    Keywords:  Allostatic load; Biomarkers; Mahalanobis distance; Physiological dysregulation; Population composition; Self-assessed health
    DOI:  https://doi.org/10.1186/s12963-022-00289-0
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