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RNA discovery provides insight into bone diseases

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RNA discovery provides insight into bone diseases

A new study has revealed that the Cpeb4 protein may have a role in regulating osteoclast differentiation, a finding that could lead to the development of new therapeutic drugs for osteoporosis and rheumatoid arthritis.

In today’s aging societies, diseases affecting the bones and joints are becoming increasingly common. For example, in Japan alone, over 12 million people suffer from osteoporosis, a condition that severely weakens bones and makes them fragile.

In order to find effective treatments for these disorders, understanding the cellular processes involved in the maintenance of bone and joint tissue is an essential first step.

Osteoclasts are a particularly important type of cell involved in bone maintenance. These cells absorb old or damaged bone and digest it, allowing the body to reuse important materials like calcium and giving way to new bones.

Various bone diseases arise when osteoclasts do not fulfill their role properly, and scientists have been investigating the mechanisms that regulate the proliferation and differentiation of precursor cells into osteoclasts.

Researchers from Tokyo University of Science (TUS), led by Professor Tadayoshi Hayata, revealed in 2020 that the cytoplasmic polyadenylation element-binding protein 4 (Cpeb4) protein is essential in osteoclast differentiation.

They also discovered that this protein, which regulates the stability and translation of messenger RNA (mRNA) molecules, transported into specific structures within the nucleus of the cell when osteoclast differentiation was induced.

However, just how this relocation occurs and what Cpeb4 exactly does within these nuclear structures still remains a mystery.

Now, in a new study, Hayata and Yasuhiro Arasaki from TUS tackled these knowledge gaps, seeking to gain a better understanding of how the “life cycle” of mRNA, i.e. mRNA metabolism, is involved.

Cpeb4 proteins

The researchers introduced strategic modifications into Cpeb4 proteins and performed a series of experiments in cell cultures, finding that the localisation of Cpbe4 in the abovementioned nuclear bodies occurred owing to its ability to bind to RNA molecules.

Afterwards, seeking to understand the role of Cpeb4 in the nucleus, the researchers demonstrated that Cpeb4 co-localized with certain mRNA splicing factors. These proteins are involved in the process of mRNA splicing, which is a key step in mRNA metabolism. Put simply, it enables a cell to produce diverse mature mRNA molecules (and eventually proteins) from a single gene.

Through RNA sequencing and gene analysis in Cpeb4-depleted cells, they found that Cpeb4 alters the expression of multiple genes associated with splicing events in freshly differentiated osteoclasts.

Through further experiments, the researchers revealed that Cpeb4 only altered the splicing patterns of Id2 mRNA, an important protein known to regulate osteoclast differentiation and development.

Overall, this study sheds important light on the mechanisms that regulate osteoclast differentiation.

“Through this research, we were able to identify important factors involved in regulating mRNA splicing during the osteoclast differentiation process and obtained new knowledge regarding the control of mRNA splicing during osteoclast differentiation,” commented Professor Hayata.

While the contribution of Cpeb4 is smaller than that of RANKL, a signaling factor that induces osteoclast differentiation, targeting Cpeb4 may have the advantage of reducing the side effects of existing drugs as too much inhibition of osteoclast differentiation with RANKL inhibitory antibodies would halt bone remodeling.

Importantly, the results contribute to a more detailed understanding of how bones are maintained.

“Although we used cultured mouse cells in our study, there are also research reports that show a correlation between variations in the CPEB4 gene and bone density in humans,” added Hayata.

“We hope that our findings will help clarify the relationship between these two in the near future.”

Most importantly, the findings of the present study may prove to be a crucial stepping stone for advancing diagnostic techniques and treatments for bone and joint diseases.

GWAS analysis has reported a correlation between single nucleotide polymorphisms in introns of the CPEB4 gene region and the estimated bone density. Therefore, it is possible that CPEB4 expression and activity can be used as diagnostic criteria.

However, the researchers note that it is unclear whether Cpeb4 actually regulates bone metabolism in vivo. Therefore, clarification of the molecular basis of Cpeb4 in bone metabolism in mice would help to establish a therapeutic approach. Additionally, recent studies have reported that Cpeb4 is expressed in various cancer cells and contributes to cancer cell survival. In cancer, Cpeb4 contributes to mRNA stability, although splicing regulation may exist.

Hayata concluded: “The discovery of part of the mechanisms by which Cpeb4 controls osteoclast differentiation could lead to the elucidation of pathologies, including osteoporosis and rheumatoid arthritis, and ultimately become the foundation for the development of new therapeutic drugs.”

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Tai chi outperforms conventional exercise for seniors

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New findings from 12 studies involving 2,901 participants have demonstrated that tai chi outperforms conventional exercise in improving mobility and balance in seniors.

While tai chi is understood to be beneficial for functional mobility and balance in older adults, such benefits are not well understood due to large variance in research study protocols and observations.

This new review and analysis has now shown that tai chi can induce greater improvement in functional mobility and balance in relatively healthy older adults compared to conventional exercise.

The findings showed the following performance results:

  • The time to complete 50-foot walking was 1.84 seconds faster. 
  • The time to maintain a one-leg stance was 6 seconds longer when eyes were open and 1.65 seconds longer when eyes were closed. 
  • Individuals improved their timed-up-and-go test performance by 0.18 points, indicating quicker standing, walking, and sitting.
  • Individuals taking the functional reach test showed significant improvement with a standardised mean difference of 0.7, suggesting a noteworthy positive impact on the ability to reach and perform daily activities.

Secondary analyses revealed that the use of tai chi with relatively short duration of less than 20 weeks, low total time of less than 24 total hours, and/or focusing on the Yang-style of this ancient form of Chinese martial arts were particularly beneficial for functional mobility and balance as compared to conventional exercise.

“This systematic literature review and meta-analysis are exciting because they provide strong evidence that tai chi is a more efficient strategy to improve functional mobility and balance in relatively healthy older adults, as compared to conventional exercise,” said Brad Manor, Ph.D., director of the Mobility and Falls Program at Hebrew SeniorLife’s Hinda and Arthur Marcus Institute for Aging Research, and associate professor of medicine, Harvard Medical School and Beth Israel Deaconess Medical Center.

“This research suggests that tai chi should be carefully considered in future studies and routines of rehabilitative programs for balance and mobility in older adults,” said Bao Dapeng, professor at Beijing Sport University.

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New standards for biomarkers of ageing

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A paper has put forward a new framework for standardising the development and validation of biomarkers of ageing to better predict longevity and quality of life.

Led by Harvard researchers, the team has zeroed in on biomarkers of ageing using omic data from population-based studies. 

The team included ageing and longevity expert Alex Zhavoronkov, PhD, founder and CEO of AI-driven drug discovery company Insilico Medicine, and the findings appeared in Nature Medicine

Ageing is associated with a number of biological changes including increased molecular and cellular damage, however, researchers do not yet have a standardised means to evaluate and validate biomarkers related to ageing. 

In order to create those standards as well as actionable clinical tools, the team analysed population-based cohort studies built on omic data (data related to biological molecules which can include proteomics, transcriptomics, genomics, and epigenomics) of blood-based biomarkers of ageing. The researchers then compared the predictive strength of different biomarkers, including study design and data collection approaches, and looked at how these biomarkers presented in different populations. 

In order to better assess the impact of ageing using biomarkers, the researchers found that clinicians needed to expand their focus to consider not only mortality as an outcome, but also how biomarkers of aging are associated with numerous other health outcomes, including functional decline, frailty, chronic disease, and disability. They also call for the standardisation of omic data to improve reliability. 

“Omics and biomarkers harmonisation efforts, such as the Biolearn project, are instrumental in validation of biomarkers of aging” said co-first author Mahdi Moqri, PhD, of the Division of Genetics. 

Biolearn is an open-source project for biomarkers of aging and is helping to harmonise existing ageing biomarkers, unify public datasets, and provide computational methodologies.

The team also emphasised the importance of continued collaborations among research groups on “large-scale, longitudinal studies that can track long-term physiological changes and responses to therapeutics in diverse populations”, and that further work is required to understand how implementation of biomarker evaluation in clinical trials might improve patient quality of life and survival.

“If we hope to have clinical trials for interventions that extend healthy lifespan in humans, we need reliable, validated biomarkers of ageing,” said co-first author Jesse Poganik, PhD, of the Division of Genetics. 

“We hope that our framework will help prioritise the most promising biomarkers and provide health care providers with clinically valuable and actionable tools.”

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Healthy aging research to receive $115 million

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Global non-profit Hevolution Foundation has announced $115 million in funding that makes up 49 new awards under its Geroscience Research Opportunities (HF-GRO) programme.  

As part of Hevolution’s mission to catalyse the healthspan scientific ecosystem and drive transformative breakthroughs in healthy aging, HF-GRO is funding promising pre-clinical research in aging biology and geroscience. 

Through this first wave of HF-GRO awards, Hevolution will invest up to $115 million in this first cohort of 49 selected projects over the next five years. Its second call for proposals under HF-GRO will be announced later this year, offering an additional $115 million to address the significant funding gaps in aging research.  

Dr. Felipe Sierra, Hevolution’s Chief Scientific Officer stated: “These 49 important research projects represent a significant step forward in deepening our understanding of healthy aging. Hevolution’s prime objective is to mobilise greater investment around uncovering the foundational mechanisms behind biological aging. 

“We are steadfast in our belief that by examining the root causes of aging, rather than solely focusing on its associated diseases, we can usher in a brighter future for humanity.” 

HF-GRO awardees include researchers at prestigious institutions across the United States, Canada, and Europe, including the U.S. National Institute on Aging, Brigham and Women’s Hospital, the Buck Institute, the Mayo Clinic, New York University, and the University of California San Francisco, among many others. 

The American Federation for Aging Research is providing programmatic support for the HF-GRO program, with grantees selected through a rigorous two-stage peer-review process involving 100 experts in aging biology and geroscience. 

Dr Berenice Benayoun, an HF-GRO grant recipient at the University of Southern California, stated: “I am extremely honored and excited that Hevolution selected our project for funding. This is a project close to my heart, which aims at understanding why and how the female and male innate immune aging differs. 

“This funding will support us as we start laying the foundation for a lasting improvement of women’s health throughout aging.” 

To date, Hevolution has committed approximately $250 million to transform the healthy aging sector, including the $40 million for specialised research and development in healthspan science recently announced at Hevolution’s Global Healthspan Summit. 

Hevolution is ramping up its investments to enable healthier aging for all and is now the second largest funder of aging biology research worldwide.  

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