bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–03–26
twelve papers selected by
Ayesh Seneviratne, Western University
  1. Hematopoietic stem cells preferentially traffic misfolded proteins to aggresomes and depend on aggrephagy to maintain protein homeostasis.
  2. A conserved role for PCYT2-regulated lipid biosynthesis in muscle health and ageing.
  3. Clonal haematopoiesis and dysregulation of the immune system.
  4. ALWAYS STRESSED BUT NEVER EXHAUSTED: HOW STEM CELLS IN MYELOID NEOPLASMS AVOID EXTINCTION IN INFLAMMATORY CONDITIONS.
  5. Morphological Analysis of Aging Hallmarks in the Central Nervous System of the Fast-Aging African Turquoise Killifish.
  6. Clonal Hematopoiesis: From Macrovascular to Microvascular Disease.
  7. Frailty from conceptualization to action: the biopsychosocial model of frailty and resilience.
  8. Growth Hormone and Aging.
  9. Endocrinology of Taste with Aging.
  10. Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: Evidences and perspectives.
  11. Obesity and Aging.
  12. Inflammaging, cellular senescence, and cognitive aging after traumatic brain injury.
  1. Cell Stem Cell. 2023 Mar 16. pii: S1934-5909(23)00071-1. [Epub ahead of print]
    Hematopoietic stem cells preferentially traffic misfolded proteins to aggresomes and depend on aggrephagy to maintain protein homeostasis.
    Bernadette A Chua, Connor J Lennan, Mary Jean Sunshine, Daniela Dreifke, Ashu Chawla, Eric J Bennett, Robert A J Signer.
      Hematopoietic stem cells (HSCs) regenerate blood cells throughout life. To preserve their fitness, HSCs are particularly dependent on maintaining protein homeostasis (proteostasis). However, how HSCs purge misfolded proteins is unknown. Here, we show that in contrast to most cells that primarily utilize the proteasome to degrade misfolded proteins, HSCs preferentially traffic misfolded proteins to aggresomes in a Bag3-dependent manner and depend on aggrephagy, a selective form of autophagy, to maintain proteostasis in vivo. When autophagy is disabled, HSCs compensate by increasing proteasome activity, but proteostasis is ultimately disrupted as protein aggregates accumulate and HSC function is impaired. Bag3-deficiency blunts aggresome formation in HSCs, resulting in protein aggregate accumulation, myeloid-biased differentiation, and diminished self-renewal activity. Furthermore, HSC aging is associated with a severe loss of aggresomes and reduced autophagic flux. Protein degradation pathways are thus specifically configured in young adult HSCs to preserve proteostasis and fitness but become dysregulated during aging.
    Keywords:  Bag3; aggrephagy; aggresome; aging; autophagy; hematopoietic stem cell; proteasome; protein degradation; proteostasis; stem cell
    DOI:  https://doi.org/10.1016/j.stem.2023.02.010
  2. Nat Metab. 2023 Mar 22.
    A conserved role for PCYT2-regulated lipid biosynthesis in muscle health and ageing.
      
    DOI:  https://doi.org/10.1038/s42255-023-00767-1
  3. Nat Rev Immunol. 2023 Mar 20.
    Clonal haematopoiesis and dysregulation of the immune system.
    Roger Belizaire, Waihay J Wong, Michelle L Robinette, Benjamin L Ebert.
      Age-related diseases are frequently linked to pathological immune dysfunction, including excessive inflammation, autoreactivity and immunodeficiency. Recent analyses of human genetic data have revealed that somatic mutations and mosaic chromosomal alterations in blood cells - a condition known as clonal haematopoiesis (CH) - are associated with ageing and pathological immune dysfunction. Indeed, large-scale epidemiological studies and experimental mouse models have demonstrated that CH can promote cardiovascular disease, chronic obstructive pulmonary disease, chronic liver disease, osteoporosis and gout. The genes most frequently mutated in CH, the epigenetic regulators TET2 and DNMT3A, implicate increased chemokine expression and inflammasome hyperactivation in myeloid cells as a possible mechanistic connection between CH and age-related diseases. In addition, TET2 and DNMT3A mutations in lymphoid cells have been shown to drive methylation-dependent alterations in differentiation and function. Here we review the observational and mechanistic studies describing the connection between CH and pathological immune dysfunction, the effects of CH-associated genetic alterations on the function of myeloid and lymphoid cells, and the clinical and therapeutic implications of CH as a target for immunomodulation.
    DOI:  https://doi.org/10.1038/s41577-023-00843-3
  4. Blood. 2023 Mar 22. pii: blood.2022017152. [Epub ahead of print]
    ALWAYS STRESSED BUT NEVER EXHAUSTED: HOW STEM CELLS IN MYELOID NEOPLASMS AVOID EXTINCTION IN INFLAMMATORY CONDITIONS.
    Helong Gary Zhao, Michael W Deininger.
      Chronic or recurrent episodes of acute inflammation cause attrition of normal hematopoietic stem cells (HSCs) that can lead to hematopoietic failure, but they drive progression in myeloid malignancies and their precursor clonal hematopoiesis (CH). Mechanistic parallels exist between hematopoiesis in chronic inflammation and the continuously increased proliferation of myeloid malignancies, particularly myeloproliferative neoplasms (MPNs). The ability to enter dormancy, a state of deep quiescence characterized by low oxidative phosphorylation, low glycolysis, reduced protein synthesis, and increased autophagy is central to the preservation of long term HSCs and likely MPN SCs. The metabolic features of dormancy resemble those of diapause, a state of arrested embryonic development triggered by adverse environmental conditions. To outcompete their normal counterparts in the inflammatory MPN environment, MPN SCs co-opt mechanisms used by HSCs to avoid exhaustion, including signal attenuation by negative regulators, insulation from activating cytokine signals, anti-inflammatory signaling, and epigenetic reprogramming. We propose that new therapeutic strategies may be derived from conceptualizing myeloid malignancies as an ecosystem out of balance, where residual normal and malignant hematopoietic cells interact in multiple ways, only few of which have been characterized in detail. Disrupting MPN SC insulation to overcome dormancy, interfering with aberrant cytokines circuits that favor MPN cells and directly boosting residual normal HSCs are potential strategies to tip the balance in favor of normal hematopoiesis. While eradicating the malignant cell clones remains the goal of therapy, this may be a more attainable objective in the short term.
    DOI:  https://doi.org/10.1182/blood.2022017152
  5. Cold Spring Harb Protoc. 2023 Mar 20.
    Morphological Analysis of Aging Hallmarks in the Central Nervous System of the Fast-Aging African Turquoise Killifish.
    Steven Bergmans, Sophie Vanhunsel, Jolien Van Houcke, Valerie Mariën, Lut Arckens, Lieve Moons.
      As the number of elderly individuals is increasing in modern society, the need for a relevant gerontology model is higher than ever before. Aging can be defined by specific cellular hallmarks, described by López-Otín and colleagues, who provided a map which can be used to scavenge the aging tissue environment. As revealing the presence of individual hallmarks does not necessarily indicate aging, here we provide different (immuno)histochemical approaches that can be used to investigate several aging hallmarks-namely, genomic damage, mitochondrial dysfunction/oxidative stress, cellular senescence, stem cell exhaustion, and altered intercellular communication-in the killifish retina, optic tectum, and/or telencephalon at a morphological level. In combination with molecular and biochemical analysis of these aging hallmarks, this protocol offers the opportunity to fully characterize the aged killifish central nervous system.
    DOI:  https://doi.org/10.1101/pdb.prot107827
  6. Arterioscler Thromb Vasc Biol. 2023 Mar 23.
    Clonal Hematopoiesis: From Macrovascular to Microvascular Disease.
    Jesse Cochran, Kenneth Walsh.
      
    Keywords:  Editorials; cardiovascular disease; clonal hematopoiesis; mutations; risk factor
    DOI:  https://doi.org/10.1161/ATVBAHA.123.319197
  7. Aging Clin Exp Res. 2023 Mar 22.
    Frailty from conceptualization to action: the biopsychosocial model of frailty and resilience.
    M Cristina Polidori, Luigi Ferrucci.
      
    DOI:  https://doi.org/10.1007/s40520-022-02337-z
  8. Endocrinol Metab Clin North Am. 2023 06;pii: S0889-8529(22)00097-4. [Epub ahead of print]52(2): 245-257
    Growth Hormone and Aging.
    Camille Hage, Roberto Salvatori.
      Growth hormone (GH) secretion declines with aging (somatopause). One of the most controversial issues in aging is GH treatment of older adults without evidence of pituitary pathology. Although some clinicians have proposed reversing the GH decline in the older population, most information comes from not placebo-controlled studies. Although most animal studies reported an association between decreased GH levels (or GH resistance) and increased lifespan, human models have shown contradictory reports on the consequences of GH deficiency (GHD) on longevity. Currently, GH treatment in adults is only indicated for individuals with childhood-onset GHD transitioning to adulthood or new-onset GHD due to hypothalamic or pituitary pathologic processes.
    Keywords:  GH deficiency; GH resistance; Growth hormone; Human aging; Somatopause
    DOI:  https://doi.org/10.1016/j.ecl.2022.10.003
  9. Endocrinol Metab Clin North Am. 2023 06;pii: S0889-8529(22)00096-2. [Epub ahead of print]52(2): 295-315
    Endocrinology of Taste with Aging.
    Chee W Chia, Shayna M Yeager, Josephine M Egan.
      Taste is one of our five primary senses, and taste impairment has been shown to increase with aging. The ability to taste allows us to enjoy the food we eat and to avoid foods that are potentially spoiled or poisonous. Recent advances in our understanding of the molecular mechanisms of taste receptor cells located within taste buds help us decipher how taste works. The discoveries of "classic" endocrine hormones in taste receptor cells point toward taste buds being actual endocrine organs. A better understanding of how taste works may help in reversing taste impairment associated with aging.
    Keywords:  Aging; Dysgeusia; Endocrine organ; Taste; Taste buds
    DOI:  https://doi.org/10.1016/j.ecl.2022.10.002
  10. Exp Gerontol. 2023 Mar 20. pii: S0531-5565(23)00075-X. [Epub ahead of print]175 112154
    Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: Evidences and perspectives.
    Saghi Hakimi Naeini, Laleh Mavaddatiyan, Zahra Rashid Kalkhoran, Soroush Taherkhani, Mahmood Talkhabi.
      Aging is a natural process that determined by a functional decline in cells and tissues as organisms are growing old, resulting in an increase at risk of disease and death. To this end, many efforts have been made to control aging and increase lifespan and healthspan. These efforts have led to the discovery of several anti-aging drugs and compounds such as rapamycin and metformin. Recently, alpha-ketoglutarate (AKG) has been introduced as a potential anti-aging metabolite that can control several functions in organisms, thereby increases longevity and improves healthspan. Unlike other synthetic anti-aging drugs, AKG is one of the metabolites of the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, and synthesized in the body. It plays a crucial role in the cell energy metabolism, amino acid/protein synthesis, epigenetic regulation, stemness and differentiation, fertility and reproductive health, and cancer cell behaviors. AKG exerts its effects through different mechanisms such as inhibiting mTOR and ATP-synthase, modulating DNA and histone demethylation and reducing ROS formation. Herein, we summarize the recent findings of AKG-related lifespan and healthspan studies and discuss AKG associated cell and molecular mechanisms involved in increasing longevity, improving reproduction, and modulating stem cells and cancer cells behavior. We also discuss the promises and limitations of AKG for delaying aging and other potential applications.
    Keywords:  ATP synthesis; Aging; Alpha-ketoglutarate; DNA methylation; Healthspan; Lifespan; mTOR
    DOI:  https://doi.org/10.1016/j.exger.2023.112154
  11. Endocrinol Metab Clin North Am. 2023 06;pii: S0889-8529(22)00095-0. [Epub ahead of print]52(2): 317-339
    Obesity and Aging.
    Noemi Malandrino, Salman Z Bhat, Maha Alfaraidhy, Rajvarun S Grewal, Rita Rastogi Kalyani.
      The obesity epidemic in aging populations poses significant public health concerns for greater morbidity and mortality risk. Age-related increased adiposity is multifactorial and often associated with reduced lean body mass. The criteria used to define obesity by body mass index in younger adults may not appropriately reflect age-related body composition changes. No consensus has been reached on the definition of sarcopenic obesity in older adults. Lifestyle interventions are generally recommended as initial therapy; however, these approaches have limitations in older adults. Similar benefits in older compared with younger adults are reported with pharmacotherapy, however, large randomized clinical trials in geriatric populations are lacking.
    Keywords:  Aging; Obesity; Sarcopenia; Sarcopenic obesity
    DOI:  https://doi.org/10.1016/j.ecl.2022.10.001
  12. Neurobiol Dis. 2023 Mar 17. pii: S0969-9961(23)00104-3. [Epub ahead of print]180 106090
    Inflammaging, cellular senescence, and cognitive aging after traumatic brain injury.
    Yujiao Lu, Abbas Jarrahi, Nicholas Moore, Manuela Bartoli, Darrell W Brann, Babak Baban, Krishnan M Dhandapani.
      Traumatic brain injury (TBI) is associated with mortality and morbidity worldwide. Accumulating pre-clinical and clinical data suggests TBI is the leading extrinsic cause of progressive neurodegeneration. Neurological deterioration after either a single moderate-severe TBI or repetitive mild TBI often resembles dementia in aged populations; however, no currently approved therapies adequately mitigate neurodegeneration. Inflammation correlates with neurodegenerative changes and cognitive dysfunction for years post-TBI, suggesting a potential association between immune activation and both age- and TBI-induced cognitive decline. Inflammaging, a chronic, low-grade sterile inflammation associated with natural aging, promotes cognitive decline. Cellular senescence and the subsequent development of a senescence associated secretory phenotype (SASP) promotes inflammaging and cognitive aging, although the functional association between senescent cells and neurodegeneration is poorly defined after TBI. In this mini-review, we provide an overview of the pre-clinical and clinical evidence linking cellular senescence with poor TBI outcomes. We also discuss the current knowledge and future potential for senotherapeutics, including senolytics and senomorphics, which kill and/or modulate senescent cells, as potential therapeutics after TBI.
    Keywords:  Aging; Immune; Inflammation; Neurodegeneration; Neurotrauma; Senescence
    DOI:  https://doi.org/10.1016/j.nbd.2023.106090
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