bims-minfam 2024-06-23 papers

Issue of 2024–06–23
eight papers selected by
Ayesh Seneviratne, Western University

Nat Aging. 2024 Jun 19.

Principal component-based clinical aging clocks identify signatures of healthy aging and targets for clinical intervention.

Sheng Fong, Kamil Pabis, Djakim Latumalea, Nomuundari Dugersuren, Maximilian Unfried, Nicholas Tolwinski, Brian Kennedy, Jan Gruber.

Clocks that measure biological age should predict all-cause mortality and give rise to actionable insights to promote healthy aging. Here we applied dimensionality reduction by principal component analysis to clinical data to generate a clinical aging clock (PCAge) identifying signatures (principal components) separating healthy and unhealthy aging trajectories. We found signatures of metabolic dysregulation, cardiac and renal dysfunction and inflammation that predict unsuccessful aging, and we demonstrate that these processes can be impacted using well-established drug interventions. Furthermore, we generated a streamlined aging clock (LinAge), based directly on PCAge, which maintains equivalent predictive power but relies on substantially fewer features. Finally, we demonstrate that our approach can be tailored to individual datasets, by re-training a custom clinical clock (CALinAge), for use in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study of caloric restriction. Our analysis of CALERIE participants suggests that 2 years of mild caloric restriction significantly reduces biological age. Altogether, we demonstrate that this dimensionality reduction approach, through integrating different biological markers, can provide targets for preventative medicine and the promotion of healthy aging.

DOI: https://doi.org/10.1038/s43587-024-00646-8

Nat Aging. 2024 Jun 12.

Conserved epigenetic hallmarks of T cell aging during immunity and malignancy.

Tian Mi, Andrew G Soerens, Shanta Alli, Tae Gun Kang, Anoop Babu Vasandan, Zhaoming Wang, Vaiva Vezys, Shunsuke Kimura, Ilaria Iacobucci, Stephen B Baylin, Peter A Jones, Christopher Hiner, April Mueller, Harris Goldstein, Charles G Mullighan, Caitlin C Zebley, David Masopust, Ben Youngblood.

Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such 'epigenetic clocks' appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination and memory T cell transplantation to test whether epigenetic aging tracks with cellular replication and if such clocks continue 'counting' beyond species lifespan. Here we found that memory T cell epigenetic clocks tick independently of host age and continue through four lifetimes. Instead of recording chronological time, T cells recorded proliferative experience through modification of cell cycle regulatory genes. Applying this epigenetic profile across a range of human T cell contexts, we found that naive T cells appeared 'young' regardless of organism age, while in pediatric patients, T cell acute lymphoblastic leukemia appeared to have epigenetically aged for up to 200 years. Thus, T cell epigenetic clocks measure replicative history and can continue to accumulate well-beyond organismal lifespan.

DOI: https://doi.org/10.1038/s43587-024-00649-5

Proc Natl Acad Sci U S A. 2024 Jun 25. 121(26): e2317945121

Calorie restriction and calorie-restriction mimetics activate chaperone-mediated autophagy.

Maryam Jafari, Adrián Macho-González, Antonio Diaz, Kristen Lindenau, Olaya Santiago-Fernández, Mei Zeng, Ashish C Massey, Rafael de Cabo, Susmita Kaushik, Ana Maria Cuervo.

Chaperone-mediated autophagy (CMA) is part of the mammalian cellular proteostasis network that ensures protein quality control, maintenance of proteome homeostasis, and proteome changes required for the adaptation to stress. Loss of proteostasis is one of the hallmarks of aging. CMA decreases with age in multiple rodent tissues and human cell types. A decrease in lysosomal levels of the lysosome-associated membrane protein type 2A (LAMP2A), the CMA receptor, has been identified as a main reason for declined CMA in aging. Here, we report constitutive activation of CMA with calorie restriction (CR), an intervention that extends healthspan, in old rodent livers and in an in vitro model of CR with cultured fibroblasts. We found that CR-mediated upregulation of CMA is due to improved stability of LAMP2A at the lysosome membrane. We also explore the translational value of our observations using calorie-restriction mimetics (CRMs), pharmacologically active substances that reproduce the biochemical and functional effects of CR. We show that acute treatment of old mice with CRMs also robustly activates CMA in several tissues and that this activation is required for the higher resistance to lipid dietary challenges conferred by treatment with CRMs. We conclude that part of the beneficial effects associated with CR/CRMs could be a consequence of the constitutive activation of CMA mediated by these interventions.

Keywords: aging; autophagy; dietary restriction; gerotherapeutics; lysosomes

DOI: https://doi.org/10.1073/pnas.2317945121

Life Sci. 2024 Jun 13. pii: S0024-3205(24)00432-6. [Epub ahead of print]351 122842

Epigenetic biomarkers in aging and longevity: Current and future application.

Mehran Izadi, Nariman Sadri, Amirhossein Abdi, Sahar Serajian, Dorsa Jalalei, Safa Tahmasebi.

The aging process has been one of the most necessary research fields in the current century, and knowing different theories of aging and the role of different genetic, epigenetic, molecular, and environmental modulating factors in increasing the knowledge of aging mechanisms and developing appropriate diagnostic, therapeutic, and preventive ways would be helpful. One of the most conserved signs of aging is epigenetic changes, including DNA methylation, histone modifications, chromatin remodeling, noncoding RNAs, and extracellular RNAs. Numerous biological processes and hallmarks are vital in aging development, but epigenomic alterations are especially notable because of their importance in gene regulation and cellular identity. The mounting evidence points to a possible interaction between age-related epigenomic alterations and other aging hallmarks, like genome instability. To extend a healthy lifespan and possibly reverse some facets of aging and aging-related diseases, it will be crucial to comprehend global and locus-specific epigenomic modifications and recognize corresponding regulators of health and longevity. In the current study, we will aim to discuss the role of epigenomic mechanisms in aging and the most recent developments in epigenetic diagnostic biomarkers, which have the potential to focus efforts on reversing the destructive signs of aging and extending the lifespan.

Keywords: Aging; Biomarker; Diagnosis; Epigenetic; Epigenome; Longevity

DOI: https://doi.org/10.1016/j.lfs.2024.122842

Front Aging. 2024 ;5 1433702

Editorial: Stem cell exhaustion in aging.

Sarallah Rezazadeh, Georgina May Ellison-Hughes.

Keywords: atac seq; exosome; hair follicle stem cell; neural stem cell (NSC); oocyte; quiescence; senscence

DOI: https://doi.org/10.3389/fragi.2024.1433702

Science. 2024 Jun 21. 384(6702): 1300-1301

Cellular senescence in normal physiology.

João Pedro de Magalhães.

Long associated with aging, senescent cells can promote health and have physiological roles.

DOI: https://doi.org/10.1126/science.adj7050

Mol Neurodegener. 2024 Jun 18. 19(1): 49

Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration.

Juan Ignacio Jiménez-Loygorri, Álvaro Viedma-Poyatos, Raquel Gómez-Sintes, Patricia Boya.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the developed world, and the number of people affected is expected to almost double by 2040. The retina presents one of the highest metabolic demands in our bodies that is partially or fully fulfilled by mitochondria in the neuroretina and retinal pigment epithelium (RPE), respectively. Together with its post-mitotic status and constant photooxidative damage from incoming light, the retina requires a tightly-regulated housekeeping system that involves autophagy. The natural polyphenol Urolithin A (UA) has shown neuroprotective benefits in several models of aging and age-associated disorders, mostly attributed to its ability to induce mitophagy and mitochondrial biogenesis. Sodium iodate (SI) administration recapitulates the late stages of AMD, including geographic atrophy and photoreceptor cell death.
METHODS: A combination of in vitro, ex vivo and in vivo models were used to test the neuroprotective potential of UA in the SI model. Functional assays (OCT, ERGs), cellular analysis (flow cytometry, qPCR) and fine confocal microscopy (immunohistochemistry, tandem selective autophagy reporters) helped address this question.
RESULTS: UA alleviated neurodegeneration and preserved visual function in SI-treated mice. Simultaneously, we observed severe proteostasis defects upon SI damage induction, including autophagosome accumulation, that were resolved in animals that received UA. Treatment with UA restored autophagic flux and triggered PINK1/Parkin-dependent mitophagy, as previously reported in the literature. Autophagy blockage caused by SI was caused by severe lysosomal membrane permeabilization. While UA did not induce lysosomal biogenesis, it did restore upcycling of permeabilized lysosomes through lysophagy. Knockdown of the lysophagy adaptor SQSTM1/p62 abrogated viability rescue by UA in SI-treated cells, exacerbated lysosomal defects and inhibited lysophagy.
CONCLUSIONS: Collectively, these data highlight a novel putative application of UA in the treatment of AMD whereby it bypasses lysosomal defects by promoting p62-dependent lysophagy to sustain proteostasis.

Keywords: Age-related macular degeneration; Autophagy; Lysophagy; Lysosomal membrane permeabilization; SQSTM1/p62; Sodium iodate; Urolithin A

DOI: https://doi.org/10.1186/s13024-024-00739-3