One of the programs undertaken by the SENS Research Foundation is to cultivate the next generation of molecular biologists and other life scientists who will work on the foundations of rejuvenation biotechnology. The future of medicine for aging will focus on manipulating, cleaning, and repairing the protein machinery of cells, using gene therapies and carefully designed molecular machines. Working to treat and prevent degenerative aging will be just another part of the broad spectrum of advanced medical research into cells and cellular machinery - but in order for that to be the case, a research community must exist. A sizable number of today's students must decide that cutting-edge longevity science is both interesting and a growth opportunity. Which it is, but you still have to sell that to people who might have inherited the old view of gerontology as a staid field of palliative clinical medicine rather than the hotbed of new knowledge that it is today, complete with barnstorming displays of hacking living cell biology.
Hence the SRF education initiative, with online coursework and a video lecture series from noted researchers. The Foundation also accepts young researchers into intern positions: these are capable undergrads and postgrads who conduct original research and help to push the current state of the art towards readiness to implement the SENS vision for rejuvenation therapies. In the process they make the connections that will help them further their future careers in this expanding field of medical research. The SENS Research Foundation is at the center of a very wide web of relationships that spans the major aging research laboratories and scientific groups of the US and beyond: it's a very good place to be seen doing good work.
Here are recent posts by some of the last set of SRF interns, discussing the SENS6 conference and looking at the work they performed at the Foundation:
Everyone knows that cancer is the result of cells multiplying out of control. Our bodies have ways of identifying these cells and destroying them. However, what goes wrong in cancer? More specifically, what happens in large tumours that allows them to evade our natural defenses? Two kinds of protein, tumour necrosis factor (TNF) and interleukin-2 (IL-2) are responsible for binding to the surface of tumour cells and inducing their death. The problem, however, is that these cells continually produce too many receptors on their surface for these proteins, then shed them, so that they effectively bypass TNF- and IL-2-induced apoptosis (cell death).
Dr Lentz presented his solution to this problem at SENS6. The therapy involves cycling the patient's blood through a device outside the body, so ligands (molecules which attach the receptors) can remove all those extra receptors in the blood. Once the procedure is complete and the blood returned to the patient, TNF and IL-2 should be able to bind to the cell-surface receptors of tumour cells and destroy them.
During her 2013 SENS Research Foundation Summer Internship, Ariana worked with the research group of Dr. William Bains at the University of Cambridge, which specializes in seeking compounds for degrading advanced glycation end-products (AGEs). AGEs are by-products of aging that accumulate in the area between cells called the extracellular matrix (ECM). The 'cross-linking' of AGEs causes wrinkles, stiff joints, hypertension, blindness, and other age-related conditions. Ariana's project focused on optimizing the decellularization step that precedes quantitation of AGEs.
"My project sought to significantly shorten the period of time required for the decellularization of tissue samples. To analyze the contribution of specific AGE cross-links to tissue aging and test possible means of breaking those cross-links, it is first important to have a quick, simple procedure for decellularizing the tissue being studied. This procedure preserves all the major ECM proteins while removing the vast majority of cellular proteins. The run-time of the original decellularization protocol was 10 days. To determine if any steps could be truncated, I measured the progress of decellularization each day during the 10-day protocol. I noted that no significant increase in decellularization occurred during several days of the protocol. Using this data, I devised a new protocol which reduces the decellularization process from 10 days down to just 3."
Ariana presented her work at the SENS6: Reimagine Aging Conference held at Queens' College, Cambridge in September 2013. The new decellularization protocol will be published in the April 2014 special edition of Rejuvenation Research.
I was particularly drawn to two presentations at the conference, that of Dr. Danica Chen from the University of California, Berkeley and that of Dr. Frank Madeo from the University of Graz. The SENS approach calls for damage repair to maintain and restore cellular function. Both presentations focused on small molecule interventions that could reverse the effects of aging.
Dr. Chen explained how sirtuin 3 (SIRT3) can slow the rate of damage to stem cells. Sirtuins are a group of seven proteins that affect many cellular processes by activating metabolic pathways. For example, sirtuins are believed to play a role in slowing the aging process via calorie restriction. However, a direct role in repair of cellular damage has remained poorly understood until now.
Another highlight of SENS6 for me was Dr. Frank Madeo's demonstration that a compound called spermidine promotes longevity. Spermidine belongs to a class of organic compounds known as polyamines, which have been shown to decline with age. They have been identified as key regulators of genes involved in aging, but the specific details as to how they interact with these genes remains unknown. Dr. Madeo noted that spermidine treatment promoted autophagy, which is the process of degrading and destroying unneeded cellular components through the lysosome. This discovery is particularly interesting to rejuvenative medicine because diminished autophagic activity is thought to play a crucial role in the aging process.
In most cases, tumor cells owe their indefinite longevity to the enzyme telomerase, which continuously extends their telomeres. However, 10 to 15% of tumor cells can maintain telomere length without telomerase function. This second method of telomere maintenance is referred to as "alternative lengthening of telomeres," or ALT. The exact mechanism by which ALT occurs remains unknown, but several chromatin remodeling genes have been implicated. Several types of cancer cells, especially in tissues of mesenchymal origin, exhibit the ALT phenomenon.
During my internship, I attempted to determine how the ALT mechanism could be overcome. Previous studies have demonstrated that a transcriptional regulator involved with chromatin remodeling, known as ATRX, is either deleted or abnormally expressed in cells which use the ALT mechanism. I hypothesized that introduction of ATRX could inhibit ALT activity. Therefore, I predicted that expression of ATRX in ALT-regulated cells would lead to a reduction in markers of ALT activity, such as C-circles, ALT-associated PML nuclear bodies (APBs), and, of course, telomere length. To test this hypothesis, I transfected three cell lines that utilize the ALT mechanism with an ATRX expression construct and measured the resulting effect on ALT activity. Preliminary data indicates that ATRX expression does indeed reduce ALT activity.