Fight Aging!

Each year the SENS Research Foundation (SRF) brings on a summer crew of young researchers, capable undergraduate and graduate life science students who perform original research to assist in building the foundations of future rejuvenation biotechnologies. This is a great opportunity for anyone interested in molecular biology and the potential for aging research to reshape itself into the largest and most important branch of medical science in the years ahead. These are the early days of the next big thing, and working with the SRF is a great way to build connections and show your worth in this field.

The Foundation staff have been posting a series on this year's interns and their thoughts on the recent SENS6 conference, and the latest few articles are up:

SRF Intern Brandon Frenz Models the Effect of Systemic Aging Factors

Aging is defined as the gradual loss of a tissue's functional stability, or homeostasis. Loss of tissue homeostasis ultimately results in tissue failure, disease, and the eventual death of the whole organism. Recent studies have shown that the rate of this decline is not an independent phenomenon but rather is regulated through systemic factors. For example, in one type of study known as heterochronic parabiosis, the circulatory systems of an old and young mouse are linked together. The reversal of several key indicators of age observed in the older mouse coupled with tissue homeostasis decline in the young mouse provides evidence that aging is regulated by systemic factors.

During my internship, I helped develop a model in the fruit fly Drosophila melanogaster to study systemically regulated aging. By creating DNA damage in a specific tissue in the fly (the primary tissue), I was able to study the effect it has on tissue elsewhere in the fly (the distal tissue). I also tested the system ex vivo (outside the fly) and was able to generate a stress response in the distal tissue when it was cultured in a media with the damaged primary tissue. The experiments I conducted during my internship indicate that our systemic aging model appears to be robust and functioning as intended. This model will now be used to determine precisely which systemic factors are driving the stress response observed in the distal tissue and ultimately better characterize how systemic signaling factors from an individual tissue can drive the rate of aging.

SRF Intern Brandon Frenz on SENS6

One presentation of particular note was given by Associate Professor of Chemistry at Yale Dr. David Spiegel. Dr. Spiegel's lab studies advanced glycation end products (AGEs). AGEs are by-products of aging that accumulate in the area between cells, called the extracellular matrix (ECM). AGEs have been implicated in a number of age-related diseases, including Alzheimer's Disease, cardiovascular disease, diabetes, and stroke. One major hurdle to develop technology to break down AGEs is obtaining sufficient chemically pure quantities for experimentation. During his presentation, Dr. Spiegel explained how his lab is chemically synthesizing AGEs, such as glucosepane, the most abundant AGE found in aged tissue, using thirteen-step synthetic sequence.

A new institute focused on protein design is being created at the University of Washington, where I am a biochemistry graduate student. I am particularly excited that synthetically designed AGE-breaker proteins easily could be tested and screened in vivo using Spiegel's breakthrough technology. I have begun talks with Dr. Spiegel about a potential collaboration and am hopeful that his synthesis protocol has provided the means to develop a method to clear glucosepane from the human body and thus alleviate some age-related diseases.

SENS6 Intern Research Award Winner Ethan Sarnoski Establishes a Link Between Senescence and Mitochondrial Dysfunction

Cellular senescence is invoked by normal dividing cells to prevent excessive cell growth. This protective mechanism prevents cells experiencing genomic stress, such as DNA damage, from becoming cancerous. However, senescent cells continue to persist and accumulate as we age. The secreted molecules from these accumulated senescent cells are hypothesized to contribute to chronic inflammation and overall aging of the organism.

Dr. Campisi's lab seeks to understand the cause of senescence as well as the effect senescence associated secreted proteins (SASPs) have on the aging process. One phenomenon associated with aging is an increased number of cells that exhibit mitochondrial dysfunction. Mitochondria are the cellular structures which convert our food into a form of cell energy known as ATP (or adenosine triphosphate) through a process called cellular respiration. ATP is produced during the final stage of cellular respiration, known as the electron transport chain. During a key step in the electron transport chain, the enzyme NADH (nicotinamide adenine dinucleotide) is oxidized into NAD+, an essential cofactor in an earlier step in cellular respiration known as glycolysis.

My research project sought to understand the role mitochondrial dysfunction can play in senescence and ultimately aging. I indeed observed that mitochondrial dysfunction is able to induce senescence in cultured cells. I also determined that the senescence response was triggered by depletion of NAD(P)+. This insight into the link between mitochondrial dysfunction and senescence is an important step in the development of interventions for preventing the accumulation of senescent cells and their adverse aging effects.

SRF Intern Ethan Sarnoski on SENS6

I'd like to tell you about one particularly engaging presentation: that of the founder and CEO of Immusoft Matthew Scholz's description of the current state of Immusoft's Immune System Programming (ISP) technology. [This] involves the genetic modification of specialized protein-secreting cells called plasmablasts. Plasmablasts are partially mature B lymphocytes with substantial but limited ability to proliferate. The Immusoft research team reprograms these cells, instructing them to secrete a therapeutic protein in addition to their normal products. Ultimately, the team hopes to translate this process to human medicine by collecting plasmablasts from a patient, modifying and expanding their numbers outside the body, and then reintroducing the modified plasmablasts as therapeutic protein factories. In other words, the Immusoft technology will program a patient's own immune cells to produce a therapeutic protein.

Preparations are currently underway for a clinical trial in collaboration with researchers at the University of California, San Francisco, where programmed plasmablasts will be used to secrete broadly neutralizing antibodies to HIV. These antibodies have been observed in HIV-resistant elite controllers, but have not been successfully elicited through conventional vaccine strategies. Production of these antibodies with ISP cells represents a promising prophylactic measure for the prevention of HIV. Further studies may allow Immusoft's ISP technology to address such issues as age-related degeneration, optimization of blood cholesterol levels, and multiple rare diseases.