Healthspan, lifespan affected differently by caloric restriction

Scientists at the Buck Institute for Research on Aging have screened more than 150 genetic strains of fruit flies that make up the drosophila genetic reference panel, and found that the effects of caloric restriction on both lifespan and activity differed by strain, and were not in lockstep. Caloric restriction is the only proven way to extend lifespan, and it has been assumed – but not experimentally verified – that this would be accompanied by an increased healthspan.

Increase or decrease in lifespan (grey bars) or healthspan (purple bars) as different fly strains underwent dietary restriction. Credit: Kenneth Wilson, PhD
The authors demonstrated that only half of the strains showed both significantly longer life and significantly higher activity, used as a proxy for good health, under caloric restriction. Thirteen percent of strains had shorter lifespans but better health, and 5% had longer lifespans but worse health. The authors also linked variants in the daedalus gene to activity, and in the decima gene to lifespan. “It is conceivable that lifespan is uncoupled from healthspan, as lifespan is likely to be affected by the weakest link that leads to changes in mortality and thus may not reflect the underlying rate of aging or a particular healthspan trait,” the authors wrote. “Understanding the genetics that modulate morbidity, particularly in response to diet, allows for more targeted approaches to maximizing healthspan.” They reported their results in the June 4, 2020, online issue of Current Biology.

Stroke protection effects like night and day

Scientists at Massachusetts General Hospital have suggested the different circadian cycles of humans and rodents as an explanation for the clinical failure of stroke medications that have been successful in animal studies. Multiple stroke drugs have failed in clinical trials, including normobaric hyperoxia (NBO), after showing neuroprotective effects in rodents. The authors tested NBO, as well as the free radical scavenger aPBN and the NMDA receptor antagonist ketamine, during both the active and the inactive phases of rodents. In each case, the drugs were successful at reducing the amount of brain damage after an experimentally induced stroke if treatment was given during the waking part of the animals’ daily cycle, but ineffective if given during their sleep cycle. Clinical trials typically recruit patients who have had strokes while awake, as it allows them to precisely establish the time of onset. “Our findings suggest that, in order to move forward, stroke mechanisms and targets should be re-assessed in rodent models with the appropriate circadian context,” the authors concluded. Their work appeared in the June 4, 2020, issue of Nature.

Oncometabolites mask DNA repair signals

Researchers at Yale University have demonstrated that mutations in metabolic enzymes made tumor cells sensitive to DNA repair inhibition via their effects on chromatin methylation. Metabolic deregulation is one of the hallmarks of cancer. Mutations in several metabolic enzymes also confer sensitivity to DNA repair inhibition by poly-(ADP-ribose) polymerase (PARP) inhibitors, through previously unknown molecular mechanisms. The Yale team showed that oncometabolites inhibited an epigenetic enzyme, lysine demethylase, leading to general hypermethylation of lysines. Trimethylation of lysines adjacent to DNA breaks is normally a signal for homology-directed repair machinery, and the hypermethylation due to inhibition of lysine demethylase essentially drowned out the trimethylated lysines near DNA breaks, leading to reduced recruitment of the DNA repair proteins ATM and TIP60. The authors wrote that “these findings provide a mechanistic basis for oncometabolite-induced HDR suppression and may guide effective strategies to exploit these defects for therapeutic gain.” Their work was published in the June 4, 2020, issue of Nature.

Antiviral vaccine protects against myocarditis, diabetes

Researchers at Karolinska Institute have demonstrated that a hexavalent Coxsackie vaccine protected mice both against Coxsackievirus infection and against type 1 diabetes. Coxsackieviruses cause hand, foot and mouth diseases, which are usually harmless. However, infections can, in rare cases, result in heart disease and meningitis. Coxsackievirus infections can also set off destruction of pancreatic islet cells and autoimmune diabetes in genetically susceptible mouse models, and likely in genetically susceptible individuals. In their work, the team showed that vaccinating mice with a hexavalent vaccine of inactivated virus protected against infection with all six known serotypes. Vaccinated animals were also protected from developing myocarditis and diabetes. “Our preclinical proof-of-concept studies demonstrate the successful generation of a promising hexavalent CVB vaccine with high immunogenicity capable of preventing CVB-induced diseases,” the authors wrote. They published their findings in the May 6, 2020, print issue of Science Advances.

C12orf49 is new lipid metabolism gene

Scientists at Rockefeller University have identified a function in cholesterol and fat metabolism for the protein C12orf49, and shown that a new form of a method called co-essentiality mapping can be used to assign functions to genes whose role is currently unknown. Co-essentiality mapping groups genes into pathways based on similar functional effects of mutations, but one challenge of the method as it is currently practiced is that it tends to false positives. The authors adapted the method to create what they termed debiased sparse partial correlation, and identified a potential role for C12orf49 in cholesterol and fatty acid metabolism. The team confirmed that prediction biochemically, and showed that depleting C12orf49 in zebrafish blocked dietary lipid clearance. In an analysis of biobank data and linked electronic health records, C12orf49 variants were linked to high blood fat levels. “Altogether, our findings reveal a conserved role for C12orf49 in cholesterol and lipid homeostasis and provide a platform to identify unknown components of other metabolic pathways,” the authors wrote. They published their study in the June 1, 2020, online issue of Nature Metabolism.

Base editing gives temporary hearing fix

Using base editing, researchers at Harvard University have restored sensory transduction in hair cells, and temporarily restored hearing, in mice that are otherwise deaf due to a recessive mutation. Base editing can precisely change single bases in a DNA sequence, which makes them an attractive method for the treatment of multiple genetic diseases that are due to single-base mutations. In their work, the authors tested the method on mice that are deaf due to a single-base mutation that leads to degeneration of the hair cells in the cochlea, which transform sound into neuronal signaling. They showed that one-time base editing on the first day of life restored auditory brainstem signaling, which is indicative of sound perception, at 4 weeks of age. However, hearing had deteriorated in two of three animals by 6 weeks of age. The authors argued that the transient nature of hearing restoration was due to insufficient levels of editing, as deteriorating cochlear hair cells can damage their neighbors. “Nonetheless,” they wrote, “these proof-of-concept data support further development of base editing for correction of point mutations that cause inherited human diseases” including genetic hearing loss.” They reported their results in the June 3, 2020, issue of Science Translational Medicine.

Simultaneous dual base editing

Meanwhile, two independent research groups have reported a technical advance in base editing that allowed them to simultaneously edit adenines and cytosines. Current base editors can either convert cytosines to thymidines, or adenines to guanines, using separate enzymes for each. Both groups fused two enzymes to the genetic targeting machinery, creating a base editor that was capable of both functions. Researchers at East China Normal University reported that their editor’s “activity on adenines is slightly reduced, whereas activity on cytosines is higher and RNA off-target activity is substantially decreased.” In contrast, the dual editor created by scientists at Tokyo University had both on-target and off-target DNA and RNA activity that were “similar to those of existing single-function base editors.” Both teams reported their results back to back in the June 1, 2020, online issue of Nature Biotechnology.

Nuclear quality control by chaperones

Investigators at the Max-Planck-Institute for Biochemistry have identified a mechanism for dealing with misfolded proteins in the nucleus. Aggregates of misfolded proteins are toxic to cells and are the hallmark of several neurodegenerative diseases, as neurons seem to be particularly sensitive to their effects. In the cell body, autophagy is the mechanism by which protein aggregates are cleared, but there is no autophagic machinery in the nucleus. The researchers identified an alternate clearance mechanism in the nucleus that was based on the protein Apj1 and heat-shock protein 70 (Hsp70). Apj1/Hsp70 disaggregated both nuclear and cytoplasmic proteins and worked in coordination with the proteasome in the nucleus, promoting degradation rather than re-folding of misfolded proteins. The authors wrote that “the Apj1-dependent coordination of disaggregation with turnover as presented here represents a mode of action whereby protein aggregates can be removed without producing toxic soluble intermediates.” They reported their results in the June 4, 2020, online issue of Cell Reports.

Stress-induced mutagenesis leads to cancer drug resistance

Researchers at the Garvan Institute of Medical Research have demonstrated that mTOR activation in cancer cells led to stress-induced mutagenesis. Tumors’ increased mutation rates help them develop resistance to drugs, but lethal mutation rates also underpin the effects of both chemotherapies and radiation. In their work, the authors demonstrated that cancer cells treated with targeted therapies had increased mutation rates, even if the therapies did not directly target DNA repair. Mechanistically, mTOR activation in tumor cells increased mutation rates by inducing a switch to error-prone DNA replication, enabling them to adapt to harsh conditions via stress-induced mutagenesis. The team concluded that their results “provide a rational framework for synthetic lethal combinations of cytostatic agents with genotoxic therapies. Such combinations could potentially generate a lethal mutational load during the initial phase of adaptive evolution, thereby reducing therapeutic failure.” They reported their findings in the June 5, 2020, issue of Science.

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