bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2023–04–30
ten papers selected by
Rich Giadone, Harvard University
  1. Protein homeostasis in the aged and diseased heart.
  2. Deletion of the Unfolded Protein Response Transducer IRE1α Is Detrimental to Aging Photoreceptors and to ER Stress-Mediated Retinal Degeneration.
  3. A distinct astrocyte subtype in the aging mouse brain characterized by impaired protein homeostasis.
  4. Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types.
  5. Heat Shock Proteins in Tooth Development and Injury Repair.
  6. Enhanced brain mitophagy slows systemic aging.
  7. In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice.
  8. CSF proteome profiling across the Alzheimer's disease spectrum reflects the multifactorial nature of the disease and identifies specific biomarker panels.
  9. Chaperone-directed ribosome repair after oxidative damage.
  10. Biological age is increased by stress and restored upon recovery.
  1. J Cardiovasc Aging. 2023 ;pii: 16. [Epub ahead of print]3(2):
    Protein homeostasis in the aged and diseased heart.
    Nirjal Mainali, Srinivas Ayyadevara, Akshatha Ganne, Robert J Shmookler Reis, Jawahar L Mehta.
      Protein homeostasis, the balance between protein synthesis and degradation, requires the clearance of misfolded and aggregated proteins and is therefore considered to be an essential aspect of establishing a physiologically effective proteome. Aging alters this balance, termed "proteostasis", resulting in the progressive accumulation of misfolded and aggregated proteins. Defective proteostasis leads to the functional deterioration of diverse regulatory processes during aging and is implicated in the etiology of multiple pathological conditions underlying a variety of neurodegenerative diseases and in age-dependent cardiovascular disease. Detergent-insoluble protein aggregates have been reported by us in both aged and hypertensive hearts. The protein constituents were found to overlap with protein aggregates seen in neurodegenerative diseases such as Alzheimer's disease. Therefore, targeting these protein components of aggregates may be a promising therapeutic strategy for cardiovascular pathologies associated with aging, ischemia, and/or hypertension.
    Keywords:  Protein aggregation; aging; cardiovascular disease; hypertension; myocardial ischemia
    DOI:  https://doi.org/10.20517/jca.2023.4
  2. Invest Ophthalmol Vis Sci. 2023 Apr 03. 64(4): 30
    Deletion of the Unfolded Protein Response Transducer IRE1α Is Detrimental to Aging Photoreceptors and to ER Stress-Mediated Retinal Degeneration.
    Dawiyat Massoudi, Seán Gorman, Yien-Ming Kuo, Takao Iwawaki, Scott A Oakes, Feroz R Papa, Douglas B Gould.
       Purpose: The unfolded protein response (UPR) is triggered when the protein folding capacity of the endoplasmic reticulum (ER) is overwhelmed and misfolded proteins accumulate in the ER, a condition referred to as ER stress. IRE1α is an ER-resident protein that plays major roles in orchestrating the UPR. Several lines of evidence implicate the UPR and its transducers in neurodegenerative diseases, including retinitis pigmentosa (RP), a group of inherited diseases that cause progressive dysfunction and loss of rod and cone photoreceptors. This study evaluated the contribution of IRE1α to photoreceptor development, homeostasis, and degeneration.
    Methods: We used a conditional gene targeting strategy to selectively inactivate Ire1α in mouse rod photoreceptors. We used a combination of optical coherence tomography (OCT) imaging, histology, and electroretinography (ERG) to assess longitudinally the effect of IRE1α deficiency in retinal development and function. Furthermore, we evaluated the IRE1α-deficient retina responses to tunicamycin-induced ER stress and in the context of RP caused by the rhodopsin mutation RhoP23H.
    Results: OCT imaging, histology, and ERG analyses did not reveal abnormalities in IRE1α-deficient retinas up to 3 months old. However, by 6 months of age, the Ire1α mutant animals showed reduced outer nuclear layer thickness and deficits in retinal function. Furthermore, conditional inactivation of Ire1α in rod photoreceptors accelerated retinal degeneration caused by the RhoP23H mutation.
    Conclusions: These data suggest that IRE1α is dispensable for photoreceptor development but important for photoreceptor homeostasis in aging retinas and for protecting against ER stress-mediated photoreceptor degeneration.
    DOI:  https://doi.org/10.1167/iovs.64.4.30
  3. Nat Aging. 2022 Aug;2(8): 726-741
    A distinct astrocyte subtype in the aging mouse brain characterized by impaired protein homeostasis.
    Eunbeol Lee, Yeon-Joo Jung, Yu Rim Park, Seongjoon Lim, Young-Jin Choi, Se Young Lee, Chan Hyuk Kim, Ji Young Mun, Won-Suk Chung.
      The aging brain exhibits a region-specific reduction in synapse number and plasticity. Although astrocytes play central roles in regulating synapses, it is unclear how changes in astrocytes contribute to age-dependent cognitive decline and vulnerability to neurodegenerative diseases. Here, we identified a unique astrocyte subtype that exhibits dysregulated autophagy and morphology in aging hippocampus. In these autophagy-dysregulated astrocytes (APDAs), autophagosomes abnormally accumulate in swollen processes, impairing protein trafficking and secretion. We found that reduced mammalian target of rapamycin (mTOR) and proteasome activities with lysosomal dysfunction generate APDAs in an age-dependent manner. Secretion of synaptogenic molecules and astrocytic synapse elimination were significantly impaired in APDAs, suggesting that APDAs have lost their ability to control synapse number and homeostasis. Indeed, excitatory synapses and dendritic spines associated with APDAs were significantly reduced. Finally, we found that mouse brains with Alzheimer's disease showed a significantly accelerated increase in APDAs, suggesting potential roles for APDAs in age- and Alzheimer's disease-related cognitive decline and synaptic pathology.
    DOI:  https://doi.org/10.1038/s43587-022-00257-1
  4. Nat Aging. 2023 Mar;3(3): 327-345
    Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types.
    Methodios Ximerakis, Kristina M Holton, Richard M Giadone, Ceren Ozek, Monika Saxena, Samara Santiago, Xian Adiconis, Danielle Dionne, Lan Nguyen, Kavya M Shah, Jill M Goldstein, Caterina Gasperini, Ioannis A Gampierakis, Scott L Lipnick, Sean K Simmons, Sean M Buchanan, Amy J Wagers, Aviv Regev, Joshua Z Levin, Lee L Rubin.
      Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell transcriptomic profiling of young and old mouse brains after parabiosis. For each cell type, we cataloged alterations in gene expression, molecular pathways, transcriptional networks, ligand-receptor interactions and senescence status. Our analyses identified gene signatures, demonstrating that heterochronic parabiosis regulates several hallmarks of aging in a cell-type-specific manner. Brain endothelial cells were found to be especially malleable to this intervention, exhibiting dynamic transcriptional changes that affect vascular structure and function. These findings suggest new strategies for slowing deterioration and driving regeneration in the aging brain through approaches that do not rely on disease-specific mechanisms or actions of individual circulating factors.
    DOI:  https://doi.org/10.1038/s43587-023-00373-6
  5. Int J Mol Sci. 2023 Apr 18. pii: 7455. [Epub ahead of print]24(8):
    Heat Shock Proteins in Tooth Development and Injury Repair.
    Shuling Guo, Haosun Yang, Jiacheng Liu, Zhaosong Meng, Lei Sui.
      Heat shock proteins (HSPs) are a class of molecular chaperones with expression increased in response to heat or other stresses. HSPs regulate cell homeostasis by modulating the folding and maturation of intracellular proteins. Tooth development is a complex process that involves many cell activities. During tooth preparation or trauma, teeth can be damaged. The damaged teeth start their repair process by remineralizing and regenerating tissue. During tooth development and injury repair, different HSPs have different expression patterns and play a special role in odontoblast differentiation and ameloblast secretion by mediating signaling pathways or participating in protein transport. This review explores the expression patterns and potential mechanisms of HSPs, particularly HSP25, HSP60 and HSP70, in tooth development and injury repair.
    Keywords:  heat shock protein; signaling pathway; tooth development; tooth injury repair
    DOI:  https://doi.org/10.3390/ijms24087455
  6. Nat Aging. 2022 Jun;2(6): 463-464
    Enhanced brain mitophagy slows systemic aging.
    Sofie Lautrup, Evandro F Fang.
      
    DOI:  https://doi.org/10.1038/s43587-022-00226-8
  7. Nat Aging. 2022 Mar;2(3): 243-253
    In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice.
    Kristen C Browder, Pradeep Reddy, Mako Yamamoto, Amin Haghani, Isabel Guillen Guillen, Sanjeeb Sahu, Chao Wang, Yosu Luque, Javier Prieto, Lei Shi, Kensaku Shojima, Tomoaki Hishida, Zijuan Lai, Qingling Li, Feroza K Choudhury, Weng R Wong, Yuxin Liang, Dewakar Sangaraju, Wendy Sandoval, Concepcion Rodriguez Esteban, Estrella Nuñez Delicado, Pedro Guillen Garcia, Michal Pawlak, Jason A Vander Heiden, Steve Horvath, Heinrich Jasper, Juan Carlos Izpisua Belmonte.
      Partial reprogramming by expression of reprogramming factors (Oct4, Sox2, Klf4 and c-Myc) for short periods of time restores a youthful epigenetic signature to aging cells and extends the life span of a premature aging mouse model. However, the effects of longer-term partial reprogramming in physiologically aging wild-type mice are unknown. Here, we performed various long-term partial reprogramming regimens, including different onset timings, during physiological aging. Long-term partial reprogramming lead to rejuvenating effects in different tissues, such as the kidney and skin, and at the organismal level; duration of the treatment determined the extent of the beneficial effects. The rejuvenating effects were associated with a reversion of the epigenetic clock and metabolic and transcriptomic changes, including reduced expression of genes involved in the inflammation, senescence and stress response pathways. Overall, our observations indicate that partial reprogramming protocols can be designed to be safe and effective in preventing age-related physiological changes. We further conclude that longer-term partial reprogramming regimens are more effective in delaying aging phenotypes than short-term reprogramming.
    DOI:  https://doi.org/10.1038/s43587-022-00183-2
  8. Nat Aging. 2022 Nov;2(11): 1040-1053
    CSF proteome profiling across the Alzheimer's disease spectrum reflects the multifactorial nature of the disease and identifies specific biomarker panels.
    Marta Del Campo, Carel F W Peeters, Erik C B Johnson, Lisa Vermunt, Yanaika S Hok-A-Hin, Mirrelijn van Nee, Alice Chen-Plotkin, David J Irwin, William T Hu, James J Lah, Nicholas T Seyfried, Eric B Dammer, Gonzalo Herradon, Lieke H Meeter, John van Swieten, Daniel Alcolea, Alberto Lleó, Allan I Levey, Afina W Lemstra, Yolande A L Pijnenburg, Pieter J Visser, Betty M Tijms, Wiesje M van der Flier, Charlotte E Teunissen.
      Development of disease-modifying therapies against Alzheimer's disease (AD) requires biomarkers reflecting the diverse pathological pathways specific for AD. We measured 665 proteins in 797 cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment with abnormal amyloid (MCI(Aβ+): n = 50), AD-dementia (n = 230), non-AD dementias (n = 322) and cognitively unimpaired controls (n = 195) using proximity ligation-based immunoassays. Here we identified >100 CSF proteins dysregulated in MCI(Aβ+) or AD compared to controls or non-AD dementias. Proteins dysregulated in MCI(Aβ+) were primarily related to protein catabolism, energy metabolism and oxidative stress, whereas those specifically dysregulated in AD dementia were related to cell remodeling, vascular function and immune system. Classification modeling unveiled biomarker panels discriminating clinical groups with high accuracies (area under the curve (AUC): 0.85-0.99), which were translated into custom multiplex assays and validated in external and independent cohorts (AUC: 0.8-0.99). Overall, this study provides novel pathophysiological leads delineating the multifactorial nature of AD and potential biomarker tools for diagnostic settings or clinical trials.
    DOI:  https://doi.org/10.1038/s43587-022-00300-1
  9. Mol Cell. 2023 Apr 18. pii: S1097-2765(23)00244-7. [Epub ahead of print]
    Chaperone-directed ribosome repair after oxidative damage.
    Yoon-Mo Yang, Youngeun Jung, Daniel Abegg, Alexander Adibekian, Kate S Carroll, Katrin Karbstein.
      Because of the central role ribosomes play for protein translation and ribosome-mediated mRNA and protein quality control (RQC), the ribosome pool is surveyed and dysfunctional ribosomes degraded both during assembly, as well as the functional cycle. Oxidative stress downregulates translation and damages mRNAs and ribosomal proteins (RPs). Although damaged mRNAs are detected and degraded via RQC, how cells mitigate damage to RPs is not known. Here, we show that cysteines in Rps26 and Rpl10 are readily oxidized, rendering the proteins non-functional. Oxidized Rps26 and Rpl10 are released from ribosomes by their chaperones, Tsr2 and Sqt1, and the damaged ribosomes are subsequently repaired with newly made proteins. Ablation of this pathway impairs growth, which is exacerbated under oxidative stress. These findings reveal an unanticipated mechanism for chaperone-mediated ribosome repair, augment our understanding of ribosome quality control, and explain previous observations of protein exchange in ribosomes from dendrites, with broad implications for aging and health.
    Keywords:  chaperone; oxidative damage; repair; ribosome
    DOI:  https://doi.org/10.1016/j.molcel.2023.03.030
  10. Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00093-1. [Epub ahead of print]
    Biological age is increased by stress and restored upon recovery.
    Jesse R Poganik, Bohan Zhang, Gurpreet S Baht, Alexander Tyshkovskiy, Amy Deik, Csaba Kerepesi, Sun Hee Yim, Ake T Lu, Amin Haghani, Tong Gong, Anna M Hedman, Ellika Andolf, Göran Pershagen, Catarina Almqvist, Clary B Clish, Steve Horvath, James P White, Vadim N Gladyshev.
      Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions. At epigenetic, transcriptomic, and metabolomic levels, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice. Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. The elevation of biological age by stress may be a quantifiable and actionable target for future interventions.
    Keywords:  aging; biological age; dynamics; epigenetic aging clocks; recovery; stress
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.015
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