“Now that we have this different hypothesis of why mitochondrial dysfunction happens during aging and age-related diseases, we open a completely different way to think about, measure, mitigate and reverse that process,” said Buck Fellow Chuankai (Kai) Zhou, PhD, who is the senior author of a study published in the March 2 issue of eLife, a leading journal on biomedical research established by the Howard Hughes Medical Institute, Max Planck Society, and Wellcome Trust.

Mitochondria are commonly referred to as the “powerhouse” of the cell, as the bean-shaped structures provide the units of energy that every cell needs to function. They are involved in many critical processes, including immune response, inflammation, and metabolism.

Dysfunction of the mitochondria is implicated in most chronic diseases, said Zhou, including neurodegenerative disorders, cardiovascular diseases, cancer, diabetes, and obesity. A growing body of evidence indicates that this dysfunction contributes to aging in general.

Zhou’s team wanted to explore the contributions of “mitochondrial biogenesis” to the dysfunction of mitochondria during aging. Mitochondrial biogenesis is the cellular process that produces new mitochondria. It determines both the quality and quantity of mitochondria in cells, both of which decline during normal aging. In the past couple decades, scientists already described two major steps of mitochondrial biogenesis: the transcriptional activation of mitochondrial protein in the cellular nucleus in response to nutrient/metabolic signals and the import of these newly synthesized mitochondrial proteins from cytosol into mitochondria. However, it was unclear how these two steps of mitochondrial biogenesis coordinate with each other to streamline the synthesis and import of mitochondria proteins. Zhou’s team found that a conserved receptor molecule on the surface of mitochondria called Tom70 might be responsible for coordinating these two steps by regulating the transcriptional activity of mitochondrial proteins inside nucleus.

Tom70 is previously known to facilitate the import of newly synthesized mitochondrial proteins. However, Zhou noted, the amount of protein created must be fine-tuned to meet the needs and import capacity of the mitochondria but not overshoot production such that excess accumulates within the cell, which damages cells and can kill them.

In the current study, his team used yeast as the model to test whether Tom70 regulates mitochondrial biogenesis by coordinating the intricate balance between the production of proteins destined for the mitochondria and the rate that these proteins can be escorted into the mitochondria. They found that it did. Similar regulatory function of Tom70 is conserved in fruit flies.

The two processes of communication about needs and uptake into the mitochondria had not been previously linked. “Our research finding that the molecule Tom70 is coordinating both aspects bridges two separate fields of study,” said Zhou.

Interestingly, they found that Tom70 declines during aging, which is associated with reduced mitochondrial biogenesis. Similar reductions of Tom70 were observed previously in aged fruit flies and rats. The team went on to show that increasing the level of Tom70 in yeast delayed mitochondrial dysfunction and increased lifespan. This finding ties in with what was known for more than a decade, that increasing Tom70 can protect human cells against some chronic diseases, such as cardiovascular disease, but the mechanistic details were not known about why this occurred. “We discovered a new function for this protein and we provide a mechanism of how Tom70 can do good things to the cell,” said Zhou.

Zhou said he can envision a number of ways in which this understanding can point to new directions in aging research. For example, the Tom70 pathway is linked to the lifespan increases seen with caloric restriction. “Additionally, if our hypothesis proves to be true, it will naturally lead to products, such as supplements or drugs. It just takes time,” he said.

For himself, Zhou said he plans to dive deeper into yeast genetics to uncover the specifics of the mechanism, such as how Tom70 communicates with the nucleus. “That is the beauty of basic research, it really gives you something to explore that did not exist before,” he said. “We are excited about translation, but we are even more excited about something brand new, that no one knew about before.”

The Penn teamexamined human cancer cells from patientswho had a history of smoking. Researchers took the cancer cells and grew them with the normal cells in the laboratory to see how small a quantity of cell could be detected. Then, with an investigational imaging agent, Cytalux™ (pafolacianine) injection, paired with Cellvizio^®, a probe and needle-based imaging platform, they discovered that integrating the technologies allowed researchers to detect cancer at the cellular level in real time during biopsy in various preclinical models, including in culture, small animal models, and human tissue from patients undergoing surgery for lung cancer as part of an ongoing clinical trial. The researchers call the new technology NIR-nCLE, as it combines the cancer-targeted near-infrared (NIR) tracer with a needle-based confocal laser endomicroscopy (nCLE) system, which is modified to detect the NIR signal.

Biopsies of suspicious tissue are not always effective, because many times the concerning nodules may be too small to see and to remove for further testing. Not only does this leave many patients and physicians uncertain about whether cancer is present, it requires the need for additional biopsies and radiological surveillance until the nodule is big enough to see for removal and evaluation via a histopathologic evaluation, which can take several days to complete. Current medical technology does not provide real-time diagnostic information during biopsy.

Methods like NIR-nCLE, which aim to find these microscopic nodules, can offer greater precision in the identification and, later, removal of cancer cells.

“The emerging ability to light up a single cell that may be invisible to the eye provides great opportunity to give patients the best chance at an early diagnosis before cancer spreads,” said Gregory T. Kennedy, MD,a resident in General Surgery at Penn. “This unique approach has the potential to improve the information we get from biopsies and it may increase our chances of identifying cancer early.”

According to the Centers for Disease Control and Prevention (CDC), lung cancer is the third most common cancer in the United States, and more people — both men and women — die from this cancer than any other type. More than 236,000 patients are diagnosed with the disease each year, and more than 130,000 people die of it annually.

“This research shines a light on the possibility of being able to more accurately identify and diagnose lesions that could be cancerous, even those that are very small and may evade our typical diagnostic capabilities,” said Sunil Singhal, MD, Chief of the Division of Thoracic Surgery, the William Maul Measey Associate Professor in Surgical Research, and director of the Center for Precision Surgery at the Abramson Cancer Center at Penn. “The quest to diagnose lung cancer in earlier stages is a centerpiece of our research, since early detection is so closely connected to chances for successful treatment.”

The researchers hope this approach can be used to help with earlier diagnosis of other cancer types. Penn investigators and industry partners have pioneered additional targeted imaging technologies for lung, brain, breast, sarcoma, head and neck, and urinary tract cancers. The U.S. Food and Drug Administration (FDA) recently approved Cytalux for use in adult patients with ovarian cancer as an add on during surgery to identify cancerous lesions.

The Center for Precision Surgery and researchers from its half-dozen affiliated labs have developed several other targeted imaging technologies since its founding in 2015. The Penn physicians and researchers have tested these approaches in clinical studies involving more than 1,200 patients at Penn to date.

In the new study, Cytalux, made by On Target Laboratories, was detected using Cellvizio^®, the real-time in vivo cellular imaging platform from Mauna Kea Technologies.

This study was funded by the National Cancer Institute (F32 CA254210-01, R01 CA193556), the American Philosophical Society Daland Fellowship in Clinical Investigation, a Thoracic Surgery Foundation Resident Research Scholarship, and the Pennsylvania Health Research Formula Fund.

The scientists’ assessment method involves measuring oxygen levels as an indicator of the extent of hypoxia and abnormal blood flow within tumors. “This study reports the development and application of a novel microscopy system with unique characteristics,” says senior author Rakesh K. Jain, PhD, director of the E.L. Steele Laboratories for Tumor Biology at MGH and the Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School. “First, this system is capable of imaging oxygen concentration both within cells and throughout large volumes of tumor tissue in relation to blood vessels, which carry the oxygen. Second, this system can image oxygen concentration in tumor tissues over time so that changes in oxygenation can be observed during therapy.”

Jain and his colleagues used their microscopy system to examine the effects of their two approaches to repair tumor blood vessel abnormalities that reduce blood flow: one using an antiangiogenic therapy that targets a pathway affecting blood vessel formation and a second that involves what are called angiotensin system inhibitors, which can alleviate the compressive forces generated by growing tumors that collapse tumor blood vessels. Losartan, a drug approved to treat high blood pressure, is an example of an angiotensin system inhibitor.

“Our microscopy analyses revealed that although each approach alleviated hypoxia in tumors, the effects were mixed — for example, having different results depending on the tumor type and dose,” says co-lead author John D. Martin, PhD, who was a PhD student in the Steele Labs during this study and is now a research scientist at Nanocarrier Co., Ltd. in Tokyo. Complementary blood vessel changes in response to the two approaches suggest the potential of combining them to create a more powerful effect.

“Understanding hypoxia in tumors — and how antiangiogenic therapy and losartan affect hypoxia — has implications for disease progression and treatment resistance,” says co-lead author Ryan Lanning, MD, PhD, who was a PhD student in the Steele Labs during this study and is now an assistant professor at the University of Colorado School of Medicine. “Antiangiogenic therapy is used as the standard of care in certain settings of lung, kidney, liver, and endometrial cancers in combination with chemo- and immunotherapy. Similarly, losartan is under clinical investigation with chemo-radiation and immunotherapy in pancreatic cancer in a multi-institutional clinical trial led by our MGH collaborators.”

The study’s co-authors include Vikash P. Chauhan, Margaret R. Martin, Ahmed S. Mousa, Walid S. Kamoun, Hee-Sun Han, Hang Lee, Triantafyllos Stylianopoulos, Moungi G. Bawendi, Dan G. Duda, Edward B. Brown, Timothy P. Padera, and Dai Fukumura.

This work was supported by the U.S. National Cancer Institute, the Department of Defense, Jane’s Trust Foundation, the Niles Albright Research Foundation, the National Foundation for Cancer Research, the Ludwig Center at Harvard, and the Rullo Family.

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The material is capable of capturing trace amounts of benzene, a toxic pollutant, from the air and crucially use less energy than existing materials to do so, according to the researchers.

The sponge-like porous material could revolutionise the search for clean air and have a significant impact in the battle against climate change, the researchers believe.

Professor Michael Zaworotko, Bernal Chair of Crystal Engineering and Science Foundation of Ireland Research Professor at University of Limerick’s Bernal Institute, and colleagues developed the new material, with findings reported in the prestigious Nature Materials journal.

Volatile organic compounds (VOCs) including benzene are a class of toxic pollutants that cause severe environmental and health issues. Developing technologies to remove benzene from air at trace concentrations and doing it with a low energy footprint are both challenges that have not been overcome until now.

“A family of porous materials — like sponge — have been developed to capture benzene vapour from polluted air and produce a clean air stream for a long working time,” explained Professor Zaworotko.

“These materials could be regenerated easily under mild heating, making them candidates for air purification and environmental remediation.

“Our materials can do much better in both sensitivity and working time than traditional materials.”

Professor Zaworotko and Dr Xiang-Jing Kong from the Department of Chemical Sciences at UL, along with colleagues from leading universities in China, developed the new porous material which has such strong affinity for benzene that it captures the toxic chemical even when present at just 1 part in 100,000.

This material resembles Swiss cheese because it is full of holes and it is these holes that attract the benzene molecules, according to the researchers.

In terms of energy, because the capture process is based upon physical rather than chemical bonding, the energy footprint of capture and release is much lower than previous generations of materials.

“Breaking up gas mixtures is hard to do. This is especially true for the minor components that comprise air, which include carbon dioxide and water. The properties of our new material show that breaking up is no longer hard to do for benzene,” explained Professor Zaworotko.

Earlier work from Professor Zaworotko’s lab resulted in leading materials for carbon capture and water harvesting. The water harvesting material has such favourable properties for capturing and releasing water from the atmosphere that is already being used in dehumidification systems.

Dr Xiang-Jing Kong explained: “Based on smart design, our materials do well in addressing challenges of both technical and social relevance, such as trace benzene removal from air. This is hard for conventional materials, and thus highlights the charm of porous materials.”

Overall, these results suggest that a new generation of bespoke porous materials of the type invented at UL can enable a general approach to the capture of toxic chemicals from air.

“Aromatic isomers are difficult to separate in their mixtures with traditional methods, which are always energy-intensive,” Dr Xiang-Jing Kong explained.

“This research opened up possibilities to design porous materials for efficient separation of these chemicals with low energy input as well as removal of other trace pollutants from air.”

The study was funded by the European Research Council and Science Foundation Ireland.

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The researchers built upon on an existing method, improving its efficiency, accessibility and quality controls. Using the new animal-free protocol, they evaluated 92 chemicals and found that their results agreed with those of a common animal test method for 77% of the compounds. The results, published today in Toxics, increase confidence in the new method’s measurements, potentially paving a route to standardization, which could both increase international trade and reduce animal testing.

Many governing bodies, including the European Union and certain U.S. states, have recently banned the sale of animal-tested cosmetics. However, animal testing is still required in some parts of the world to assess the safety of cosmetics. With regulations varying by region, it has become challenging for certain products to gain approval across the board.

Some animal-free methods of screening for skin allergens do exist, but their widespread adoption has been stymied by several limitations. For example, the direct peptide reactivity assay (DPRA) requires costly equipment that can only test a handful of samples at a time. The DPRA can be slow as well. To attain statistically meaningful conclusions about a test compound, testers would need to repeat the assay’s multiday process multiple times.

The low sample size per test also reduces opportunity for control samples that would allow researchers to identify and minimize factors that may vary between samples and skew measurements.

To increase confidence in animal-free tests and promote their adoption, several federal agencies, coordinated by a standing committee of the National Institute of Environmental Health Sciences, are assessing the reliability of new, promising methods. The CPSC, a member agency of the committee, has partnered with NIST to evaluate a method much faster than the DPRA, known as the electrophilic allergen screening assay (EASA).

The EASA can be used to determine how reactive a chemical would be with human skin proteins, that is, how likely it would be to cause an allergic response. No actual proteins, or the amino acids they are made from, are present in the test. Instead, the researchers use two probe molecules, 4-nitrobenzenethiol (NBT) and pyridoxylamine (PDA), which, when reacting with other chemicals, undergo changes that can be detected optically.

“The two molecules are like surrogates for the amino acids cysteine and lysine,” said Elijah Petersen, a NIST research scientist and lead author of the paper. “If a test compound binds to NBT and PDA, it is likely to also bind to the proteins in the skin, which is the first step of many adverse reactions.”

Although the initial version of EASA showed promise, the NIST and CPSC researchers found it shared weaknesses with the DPRA, Petersen said. The type of instruments needed to run the original EASA method typically only hold up to eight samples at a time and are not readily available to most biological labs.

Petersen and colleagues reconfigured EASA so that 96 samples could be analyzed in a single run using plastic well plates and instruments called plate readers — two ubiquitous items in biological labs.

With up to 96 wells to work with, the researchers redesigned the protocol so that many control wells could be tested alongside wells containing test compounds. The controls would allow researchers to find out whether factors such as the solvent used, air bubbles in samples or the optical properties of the test compounds interfered with their measurements.

“In this one assay, we have much of the information we need to understand the sources of variability,” Petersen said. “I think we really capture more and have more confidence compared to other methods.”

To validate their redesigned protocol, the researchers used the new EASA to analyze 92 test compounds. Most of the chemicals had been assessed in previously published studies on mice through a standard test called the local lymph node assay (LLNA).

They found that the LLNA and EASA results agreed 77% of the time on which chemicals were allergens and which ones were not. Individual EASA tests were completed within a day, while LLNA tests require at least five days, Petersen said.

The new EASA also performed similarly to the DPRA, while testing samples at a higher rate and with more accessible equipment.

This work provides a robust methodology for evaluating the safety of cosmetics without animals. With further validation, the EASA could become a viable candidate for standardization and eventual adoption by regulatory bodies, according to Petersen.

“This study could support testing of commercial products, because we’re going to have a really good method that’s cheaper, faster, better quality,” Petersen said. “I think it could also help raise the quality of in vitro test systems in general if people adopt our approach of adding extensive process controls.”

The condition is one of the most common and serious valve disease problems, caused by a narrowing of the aortic valve opening.

Once patients develop symptoms such as breathlessness, chest pains or blackouts then guidelines recommend replacing the narrowed valve. But many patients with aortic stenosis do not have symptoms even when they have severe narrowing of the valve and are thus not eligible for valve replacement.

New research published today shows that these patients would benefit by undergoing a valve replacement — before they suffer irreversible heart muscle damage.

Lead researcher Prof Vassilios Vassiliou, from UEA’s Norwich Medical School, said: “The heart has four valves, which allow the blood to flow in one direction efficiently. With increasing age, one of the valves, the aortic valve, becomes increasingly narrowed or ‘stenosed’.

“A lot of patients with severe aortic stenosis do not have symptoms and therefore are not eligible for valve replacement according to the current guidelines.

“For these patients without symptoms, the guidelines suggest a ‘watchful waiting’ approach and intervention is recommended only when they show symptoms or develop pump failure.

“We wanted to know if it would be better to perform surgery and replace the valve sooner rather than later.”

The research team carried out a systematic review and meta-analysis, comparing early intervention versus conservative management in patients with asymptomatic severe aortic stenosis.

They then analysed data from all the available studies which involved a total of 3798 patients, out of which 302 were included in the two largest randomised controlled trials and 3496 in the observational studies.

Prof Vassiliou said: “We found that early intervention, before patients have symptoms, is associated with lower risk of death and hospitalisation for heart failure.

“By the time the patients develop symptoms, there has likely been irreversible damage to the muscle of the heart. This in turn may preclude a worse prognosis and adverse outcomes even after successful intervention.

“The timing of aortic valve intervention is crucial.

“We hope that our findings may herald the beginning of a change in the management of aortic stenosis patients, enabling the intervention to take place more commonly whilst the patients are asymptomatic.

“Ongoing trials investigating this high-risk population are anticipated to shed more light into the matter and in the identification of the optimal time of intervention,” he added.

The research was carried out in collaboration with the University of Cambridge, the University of Edinburgh, the Norfolk and Norwich University Hospital, West Suffolk Hospital, the Royal Brompton and Harefield Hospitals, Imperial College London, and the University of Leicester. It was partly funded by the Wellcome Trust.

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