Aging news

Senescent cells exhibit depletion of metabolites from nucleotide synthesis path- ways. Stable isotope tracing with 13C-labeled glucose or glutamine revealed a dramatic blockage of flux of these two metabolites into nucleotide synthesis pathways.  Blocking the pathway in replicative cells induces senescent phenotype.

Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells. May28, 2019.  JBC. Alireza Delfarah, Sydney Parrish, Jason A. Junge, Jesse Yang, Frances Seo, Si Li, John Mac, Pin Wang, Scott E. Fraser, and X Nicholas A. Graham. DOI10.1074/jbc.RA118.005806. 

We report that naked mole-rat fibroblasts have significantly increased translational fidelity despite having comparable translation rates with mouse fibroblasts.
Naked mole-rat has increased translational fidelity compared with the mouse, as well as a unique 28S ribosomal RNA cleavage. Azpurua J, Ke Z, Chen IX, Zhang Q, Ermolenko DN, Zhang ZD, Gorbunova V, Seluanov A. Proc Natl Acad Sci U S A. 2013 Sep 30.

Anti-Aging treatments — human
Removing senescent cells
Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study“. (2019)
Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice. A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention.
Results: no clear benefit.

Stem cells
Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial” (2017).
100M – 200M intravenous allo-hMSCs from young donors in old patients, 10 each group.
Results: no significant improvement.

Anti-Aging treatments — mouse
Removing senescent cells
The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs“. (2015)
The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1−/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose.
Result: Improves phenotype of old mice. Does not increase maximum lifespan.

Senolytics Improve Physical Function and Increase Lifespan in Old Age“. (2018)
Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally-occurring senescent cells and their secretion of frailty-related pro-inflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted younger and naturally-aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%.
Result: Improves phenotype of old mice. Does not increase maximum lifespan.

Lifespan extension — human
A null mutation in SERPINE1 protects against biological aging in humans
43 hets for a SERPINE1 null have a mean lifespan of +7 years, p=0.04 and 10% longer telomeres. Maximum lifespan was wt. SERPINE1 encodes Plasminogen activator inhibitor–1 (PAI-1), thought to be pro-senescent.

Lifespan extension — model organisms
Longevity gene’ responsible for more efficient DNA repair
SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species” (2019)
SIRT6 activity levels in different rodents correlate with lifespan. “mice with extra copies live longer”
MDL-800, an allosteric activator of SIRT6, suppresses proliferation and enhances EGFR-TKIs therapy in non-small cell lung cancer

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