Fight Aging!

Each year, the SENS Research Foundation accepts a group of young life science academics and puts them to work on projects in aging research, both at the foundation and in allied laboratories, creating ties between research groups that can help to advance the state of the art. This year's batch has worked on a diverse set of projects that spread out beyond core SENS initiatives such as allotopic expression of mitochondrial genes. Reading through their projects is a reminder that a great deal can be accomplished these days given a small team, a little funding, and an equipped laboratory. Progress in medical research is no longer restricted to very large and very well funded groups: with a postgraduate, a few tens of thousands of dollars, and a few months, it is in fact possible to meaningfully contribute to the field. There is so very much still to accomplish when it comes to bringing methods of rejuvenation to the clinic, but a large fraction of these line items can in fact be helped towards realization by such modest, individual efforts. Early stage research, building the proof of concept and the prototype, has fallen in cost dramatically. The tools of the trade are far cheaper and far more capable than even a decade ago, and knowledge of cellular biochemistry has expanded just as dramatically. This trend will continue.

Just as important as getting things done is to expand the population of researchers who view aging as a medical condition, and who are sympathetic to the model of aging as damage accumulation, and thus also to the goal of therapies based on repair of that damage. The defeat of aging, the construction of a comprehensive package of rejuvenation therapies, is a long term project. The research teams putting the finishing touches to the last of the first generation repair therapies, perhaps twenty years from now, will be led by people who are still in college today. The concept of aging as a reversible medical condition can only be made normal and desirable in the eyes of a world that has rejected this idea by involving ever more people in the research community, among patient advocates, in the population at large. This is as much a matter of education of the next generation as it is of persuasion of the current generation. When considering the scale of the medical industry needed to provide effective means of rejuvenation, given that every adult over the age of 40 will be a repeat customer, it is clear that the whole of the field today, for all its growth, is still just in the earliest stages of bootstrapping. This is the most appropriate time to be building foundations for the long-term.

2017 SRF Summer Scholar Profile: Amelia Anderson

Here at the SENS Research Foundation, I have been working with derivatives of drugs which have been shown to solubilize cholesterol and/or harmful derivatives of cholesterol such as oxysterols. Cholesterol and its harmful derivatives are taken up by cells as they attempt to process these molecules for the body. As macrophage lysosomes become more and more saturated with debris from cholesterol molecules, the cells become useless and form foam cells when they can no longer process the excess cholesterol. These malfunctioning foam cells accumulate in the arterial walls, becoming part of the problem instead of the solution and contributing to the plaques which cause atherosclerosis, or hardening of the arteries. In order to develop a safer, more effective treatment for atherosclerosis, a rational drug design venture is underway at SENS. Various tests have been and will be conducted with novel drugs for the purpose of removing cholesterol and its derivatives from atherosclerotic plaques. For my project, experiments have been designed to assess the effectiveness and safety of these drugs for the purpose of reducing atherosclerotic plaques in human arteries.

2017 SRF Summer Scholar Profile: Sumedh Sontakke

Historically, the pharmaceutical industry's mode of operation is to rely on blockbuster drugs by conducting expensive clinical trials followed by marketing in developed economies if the trials are successful. Unfortunately, this tactic isn't working very well. My research project will attempt to use machine learning methods to improve this dismal statistic. How? Machine learning is a tool that helps us understand how several quantities are related to one another purely on the basis of the data provided. It challenges preconceived notions about factors that influence an output. And, in the field of drug development, this is what is needed given the abysmal attrition rate and burgeoning costs. The algorithms that I will employ will highlight the factors that influence the probability that a drug will clear clinical trials. I plan on predicting the launch or failure of new molecular entities using a model that takes a holistic approach with regards to which variables affect drug success.

2017 SRF Summer Scholar Profile: Alefia Kothambawala

Growing up, I hardly thought of aging as a disease as opposed to a natural result of life. However, as I focused on muscle atrophy during a summer internship, I soon saw the larger scope of the problem. After this experience, I sought to better understand tissue growth, wanting to branch out beyond atrophy. Though Alzheimer's Disease (AD) is a dementia characterized by deficits in memory, spatial skills, and language, over half of AD patients also display psychotic symptoms. The shared psychiatric symptoms between schizophrenia and AD suggest common molecular pathophysiology. Furthermore, previous research has shown that the two diseases bear similarities in neural pathology and biochemical dysfunction. Thus, it would be of interest to study the novel use of antipsychotics, particularly clozapine, to investigate AD psychosis. As a SRF Summer Scholar, I will be working to explore the relationship between AD, clozapine, and CRMP2.

2017 SRF Summer Scholar Profile: Tianhan Deng

Prior to joining the SRF Summer Scholars Program, I was heavily involved in a research project aimed at understanding the biology of low-grade gliomas. My project this summer aims to create the best model for lung-to-brain cancer metastasis. Secondary brain metastases are a devastating condition, bearing a dismal prognosis. A large number of brain metastases originate from lung carcinomas, specifically non-small cell lung adenocarcinomas. Due to its complicated biology and tendency to metastasize, it remains one of the deadliest tumors in the field and has posed a great challenge in finding a cure. A promising step toward finding a cure has been the discovery of TRAIL (Tumor Necrosis Factor-Related Apoptosis Inducing Ligand). TRAIL produce anti-tumor effects by causing tumor cells to essentially "suicide," and its specificity for tumor cells but not healthy cells makes it a great therapeutic approach. My project will focus on selecting a good model to recapitulate the biology of metastatic lung adenocarcinoma and gather the preclinical data for a modified TRAIL as a therapy.

2017 SRF Summer Scholar Profile: Shil Patel

This summer, I will explore stem cell treatment for Parkinson's disease (PD). I will be assessing the genotypes of induced pluripotent stem cell (iPSC) lines from 10 patients with PD to evaluate their genomic integrity. Single nucleotide polymorphisms (SNPs) are common sites of genetic variation between humans. By determining the precise nucleotide at common sites of variation, we begin to get a picture of the genome, and the more SNP sites we examine, the more the resolution of the genomic picture increases. I will load patient skin cell and iPSC DNA onto a microarray chip that can detect the nucleotide identity at 4.3 million SNPs across the genome and use bioinformatics software to identify variations. The results will indicate which of the stem cell lines from each patient are safe to use for transplanting neurons. Using SNP microarrays to assess genomic integrity represents a high throughput quality control testing that can be used to safely create functional neurons from the cells of patients that require no immunosuppression after transplantation.

2017 SRF Summer Scholar Profile: Jasmine Zhao

This summer, my project is to design and test different constructs that can potentially improve the allotopic expression of ATP6 to mitochondria in mutant cell lines. Mitochondria are double-membrane bound organelles that provide energy in the form of ATP to power the biochemical reactions of a cell. Unlike other organelles, however, mitochondria have their own DNA separate from the nucleus, and 13 out of those 37 genes encode for oxidative phosphorylation complex proteins. Due to possible leakage of the high-energy electrons of the respiratory chain, which results in the formation of reactive oxygen species, the oxidative stress mitochondrial-DNA (mtDNA) is subjected to can lead to mutations, aging, and cell death. For instance, the mutations of ATP6 have been implicated in different human diseases that affect neural development, vision, and motor movement.

Allotopic expression has been proposed as a gene therapy approach that can potentially treat mitochondrial-DNA diseases. This method aims to express a wild-type copy of an affected mitochondrial gene in the nucleus of a cell, target it to the mitochondria, and allow functional replacement of the defective protein. Stable allotopic co-expression of ATP8 and ATP6 is able to rescue a cell line that is null for the ATP8 protein and has significantly lowered ATP6 protein levels. However, improving the exogenous amount of ATP6 that can be expressed or targeted to the mitochondria may be necessary in order to achieve complete restoration. Therefore, my project will investigate whether appending an additional gene sequence, the soluble tag, can help stabilize ATP6 and prevent unfolding before it is inserted into mitochondria.

2017 SRF Summer Scholar Profile: Srinidhi Venkatesan Kalavai

Through the SRF Summer Scholars Program, I will be studying the TOR pathway in intestinal stem cells of fruit flies to understand the effect of metabolism on stem cell function. The TOR pathway is involved in cell growth by regulating protein synthesis and metabolism, autophagy, transcription and ribosome biogenesis. The TOR pathway seems to be critical for both the proliferation and differentiation of stem cells and is regulated by many different mechanisms. It has been shown that nutrients can regulate TOR, but the exact molecular mechanism involved in regulating TOR is unknown. Thus, the goal of this project is to better understand the molecular mechanisms that are responsible for TOR activation in intestinal stem cells in response to injury.

2017 SRF Summer Scholar Profile: Anja Schempf

Autophagy is the process by which cells degrade old and damaged organelles and proteins, allowing the cells to prevent damage inflicted by these impaired components. In humans, autophagy helps to prevent the aging of cells, but levels of autophagy tend to diminish as we age. When autophagy levels are lower, muscle disorders and heart issues can occur. My goal this summer is to discover the effect of spermidine, a natural polyamine which has been shown to increase mouse lifespan, on liver tissue and to understand whether spermidine acts in the same way as another autophagy-inducing chemical, rapamycin. The main two protein complexes I will be focusing on are mTORC1 (mechanistic target of rapamycin) and mTORC2, which are protein complexes that regulate autophagy and cell regulation as well as cell metabolism. While the drug rapamycin has been shown to reduce autophagy by lowering levels of mTORC1 and therefore elevating autophagy, it is unclear if spermidine acts through the same pathway, despite producing the same effect. By testing mTOR levels, I will be able to discover whether spermidine acts using the same pathway as rapamycin.

2017 SRF Summer Scholar Profile: Michaela Copp

This summer, I will be working with the SRF Mitochondrial Team. Mitochondria generate the cellular energy consumed by mammalian cells through the process of oxidative phosphorylation. Like the nucleus, mitochondria possess their own DNA, termed mtDNA, which encode for 13 proteins critical to cellular respiration. Unfortunately, mitochondria do not have an efficient system for repairing damaged DNA, leading to mutation rates 10 times greater than that detected in nuclear DNA. Scientists believe evolutionary forces have driven mitochondrial genes from the mitochondria into the nucleus, where they are protected from the highly-reactive oxygen molecules produced by oxidative phosphorylation. The SRF Mitochondrial team hopes to mimic this evolutionary process by providing cells with a modified "backup" copy of the remaining mitochondrial genes at a safe harbor within the nucleus. The procedure of expressing genes in the nucleus originating from the mitochondria is called allotopic expression. Prior to this project, allotopic expression studies on mitochondrial genes had been performed via traditional transfection / virus induction procedures which integrate the new DNA randomly into the host genome. The goal of this study is to express the mitochondrial genes from an identified safe-harbor site in the nucleus in order to minimally disrupt the host genome and ensure the gene functions predictably.

2017 SRF Summer Scholar Profile: Heather Tolcher

I am concentrating my efforts on determining the regenerative process of the heart, focusing on the epicardium. Certain animal species, such as zebrafish, can fully repair cardiac tissue that is lost by injury. In adult zebrafish, activation of the epicardium is observed during the immediate response to tissue damage. This summer, I will be investigating the regulatory sequences that are differentially accessible in the regenerating adult epicardium based on ATAC-seq data. This ATAC-seq data shows which chromatin regions on a specific gene are open and accessible and which regions may possibly act as regenerative enhancers on the epicardium. By selecting certain open chromatin regions at different stages of the regenerative process and by performing perturbation experiments in zebrafish, we aim to further elucidate epicardial contributions during cardiac regeneration. By more thoroughly understanding the molecular events that drive cardiac regeneration, we may be able to provide a new perspective and mechanism for clinical intervention after myocardial infarction.

2017 SRF Summer Scholar Profile: Aashka Patel

My project this summer will explore neuronal circuit connectivity of hiPSCs (cells reprogrammed to become embryonic-like stem cells that can differentiate into various cell types) derived from Alzheimer's Disease (AD) neurons. We are going to investigate how Alzheimer's disease affects neural circuitry and the complexity of communication between affected neurons. Firstly, we will obtain a line of AD stem cells and differentiate them into neurons. AD neurons will be cultured and investigated in a multielectrode array (MEA) plate. This relatively new technology allows measurement of individual neuron depolarization. Using data obtained from MEAs, we can analyze the complexity and duration of communication between neurons. Compared to data collected from an unaffected line of neurons, changes in duration and frequency of bursts (synchronized firing of neurons) can inform us about the complexity of information transferred between neurons.

2017 SRF Summer Scholar Profile: Yujie Ma

My projects will use Drosophila melanogaster, better known as fruit flies, as a model system. In my first project I will investigate the role of a member of the sirtuin family in regulating protein homeostasis (proteostasis) in intestinal stem cells (ISCs). My second project will assess whether altering proteostasis in ISCs influences the proteostasis of cell types found in different tissues. For the cell to remain healthy there must be a fine balance between synthesis/degradation and refolding of misfolded or elimination of damaged proteins. The most common mechanisms a cell can employ to degrade damaged proteins are via proteasome or autophagosome. Unfortunately, aging causes a decline in proteostasis; protein aggregates are more likely to form in certain cells of older organisms. I am interested in understating how adult somatic stem cells (SCs) maintain proteostasis, and I will use Drosophila intestinal SCs (ISCs) as a model system to study proteostasis in adult somatic SCs.