sirtuin sirt1 involved in cytoxic t cells

This Anti-Aging Protein Could Be Targeted to Rejuvenate Our Immune Cells

Summary: Scientists discover that the anti-aging protein SIRT1 could be targeted to rejuvenate T cells in our aging immune systems.  [Author: Brady Hartman] This article first appeared on LongevityFacts.]

Anti-aging proteins in the sirtuin family have long been shown to protect against age-related diseases, such as cardiovascular disease, cancer, and neurodegeneration. A new research study by scientists at the Gladstone Institutes now reveals that the protein called SIRT1 could also be targeted to rejuvenate aging immune system cells. SIRT1 is commonly known for being activated by naturally occurring substances found in red wine.

Melanie Ott and Philip Ansumana Hull reveal what happens to cytotoxic T cells when the immune system ages.
Melanie Ott and Philip Ansumana Hull reveal what happens to cytotoxic T cells when the immune system ages. Photo courtesy of Gladstone Institutes

In the new study, published Wednesday in the Journal of Experimental Medicine, the researchers found that SIRT1 is also involved in how immune system cells develop with age. The Gladstone scientists wanted to find out how the anti-aging protein SIRT1 affects the immune cells known as cytotoxic T cells. Also called killer T cells, these cells are highly specialized guardians of the immune system, and their role is to kill cancer cells, damaged cells, or those cells infected by a virus. More specifically, a cytotoxic T cell is a type of white blood cell and also a type of lymphocyte. To treat tumors, these can be separated from other blood cells, grown in a laboratory, and then given to a patient to kill cancer cells. Melanie Ott, a senior author of the new study, and a Gladstone Senior Investigator said

“Over the course of a person’s life, with repeated exposure to bacteria and viruses, these T cells mature and eventually lose a protein called CD28,” adding “And as these cells get older, they become more toxic to their environment.”

This aging process is accelerated by chronic viral infections, such as HIV and human cytomegalovirus (CMV). In fact, HIV-infected patients accumulate mature cytotoxic T cells at a much younger age than uninfected individuals. Ott says,

“A higher number of mature cytotoxic T cells in the body has been associated with age-related, autoimmune, and inflammatory diseases,” adding “We wanted to come up with a way to counteract this phenomenon.”

The cytomegalovirus is a member of the herpes virus family. A CMV infection stays in the body for life and only causes noticeable problems with newborn babies, pregnant women, and people with weak immune systems.

The CMV virus infects more than half the population, with infection rates increasing as we grow older.  One study in 2004 reported that more than 90% of people aged 80 and older were positive for CMV infection.

While CMV infection is generally without symptoms in most people, it causes trouble by tying up our immune systems. Some scientists say that persistent CMV infection contributes to the chronic inflammation of aging called inflammaging, a term popularized in the scientific literature by the leading geroscientist, Claudio Franceschi.

What Happens in Aging Killer T Cells

When an immature T cell is in a resting state, it uses oxygen to breathe. Once the immune cell is activated to defend the body against a pathogen, such as a virus or bacteria, it shifts into enhanced glycolysis and uses glucose to get an immediate boost in energy. The sugar provides a quick spurt of energy, but can’t sustain long-term performance. Melanie Ott says,

“You can think of it like a 60-meter sprint runner who needs a quick boost of energy to finish the race, in comparison to a marathon runner who needs different energy sources to keep going for a long period of time.”

As cytotoxic T cells age and lose CD28, they can shift into glycolysis much more quickly if their breathing is inhibited. The aging immune cells also lose the anti-aging protein SIRT1 and this makes them more toxic to the cells around them.

In the new research study, Ott and her colleagues explain how this all happens. Philip Ansumana Hull, a graduate student in Ott’s lab and one of the first authors of the study says

“We studied human T cells, isolated from blood donors of all ages, to compare mature cytotoxic T cells with naive ones.”

The scientists found that naive T cells have a high concentration of SIRT1, a member of the family of proteins and genes called sirtuins. This stabilizes the mechanism that prevents the T cells from entering into glycolysis and limits their toxic effects. However, as T cells age, they lose SIRT1, which alters their basic metabolism. The aging immune cells are more likely to rapidly shift into glycolysis and start producing more toxic and pro-inflammatory proteins called cytokines, which, in turn, could lead to inflammatory diseases.

One Mechanism to Fight Aging and Aggressive Cancers

Based on a better understanding of the crucial role played by SIRT1 in the aging of T cells, the scientists identified two potential novel drug targets. The first target is new drugs which could be developed to strengthen SIRT1 to rejuvenate mature cytotoxic T cells or keep them from progressing too rapidly into the highly toxic state. Mark Y. Jeng, the study’s other first author and former graduate student in Ott’s lab says,

“This could postpone the development of age-related diseases,” adding “It could also help people with a weaker immune system fight infections or better respond to immune vaccination, such as seniors or chronically-infected patients.”

Alternatively, drugs could aim for the opposite effect and encourage the T cells to be more toxic. By temporarily making immature T cells more aggressive and behave like mature ones, for example, they could support an aggressive anti-tumor response or other immune therapies. An immune therapy is a type of biological therapy that uses substances to suppress or stimulate a patient’s  immune system to help them fight infection, cancer, and other diseases.

Sirtuin SIRT1

SIRT1 is a member of the family of genes called sirtuins.  Sirtuins are a family of proteins, genes, and enzymes which affect multiple pathways that increase the lifespan and the overall health of organisms. SIRT1 was the first known mammalian sirtuin discovered, in the early 2000’s. Since enzymes are proteins and genes code for proteins, SIRT1  is interchangeably referred to a gene and as a protein.

Geroscientists have linked sirtuins to influencing a wide range of cellular processes like aging, cellular stress resistance, inflammation, transcription, and apoptosis (cell death).  As well, scientists have linked sirtuins to energy efficiency and alertness during the low-calorie situations that occur during intermittent fasting and calorie restriction, although the relationship is controversial. Sirtuins can also control the creation of new mitochondria and circadian clocks.

Sirtuins have been linked with the compound nicotinamide adenine dinucleotide (NAD) – one of the compounds heralded as being able to beat aging in our lifetimes. However, the relationship is complex.

SIRT1 is mostly involved in metabolism and inflammation. According to a 2014 review by Weiwei Dang, evidence suggests that SIRT1 is profoundly involved in cancers, apoptosis, neuroprotection against various neurodegenerative diseases, such as Alzheimer’s and Parkinson’s; promoting liver function and regeneration; stem cell differentiation and cell fate determination; and delaying replicative senescence in primary fibroblasts.

Resveratrol has long been heralded as a sirtuin activator, and whether the claim is true is the subject of much debate.  According to Dang,

“Although resveratrol’s function as a sirtuin activator is under debate, the compound rising with the fame of sirtuins did show many health benefits in clinical trials.”

Bottom Line: It seems that many things are controversial about sirtuins, such as their positive health benefits and the things that activate them.

Boosting the Immune System by Regrowing the Thymus

One scientist thinks he may have found a better way of boosting our immune systems – by regrowing our thymus.

In fact, Dr. Greg Fahy reported ‘successful’ interim results of a clinical trial to regrow the thymus in otherwise healthy middle-aged men.

As we age, our immune system declines, which in turn causes increased rates of cancer and infections in older adults.  One reason for this decline is our thymus. This organ in our chest produces fresh T cells, however beginning in young adulthood, the thymus shrinks drastically, starting to collapse by our 50’s. Our aging bodies must then depend on the bounty of T cells that we produced in our youth. Unfortunately, these T cells become increasingly used up to fight chronic infections such as CMV and other infections.

The ideal solution would be to have a supply of fresh young T cells, however, none are forthcoming, because our thymus has shriveled after middle age.

Prominent researcher Dr. Greg Fahy may have found a solution. Dr. Fahy just announced preliminary results of a clinical trial which shows that restoring thymus function – by regrowing the organ – might be done safely and effectively.

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Cover photo: man_at_mouse / Getty Images.

Julie Langelier. “An Anti-Aging Protein Could Be Targeted to Rejuvenate Immune Cells.” Gladstone News – Gladstone Institutes. [Press Release]. November 30, 2017. Link.

Mark Y. Jeng, Philip A. Hull, Mingjian Fei, Hye-Sook Kwon, Chia-Lin Tsou, Herb Kasler, Che-Ping Ng, David E. Gordon, Jeffrey Johnson, Nevan Krogan, Eric Verdin, Melanie Ott. “Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1.” Journal of Experimental Medicine. Nov 2017, jem.20161066; DOI:10.1084/jem.20161066. Link.

Stephanie A. S. Staras, Sheila C. Dollard, Kay W. Radford, W. Dana Flanders, Robert F. Pass, Michael J. Cannon; “Seroprevalence of Cytomegalovirus Infection in the United States,” 1988–1994, Clinical Infectious Diseases, Volume 43, Issue 9, 1 November 2006, Pages 1143–1151, Link. 

Haigis, Marcia C., and David A. Sinclair. “Mammalian Sirtuins: Biological Insights and Disease Relevance.” Annual review of pathology 5 (2010): 253–295. PMC. Web. 1 Dec. 2017. Link.

Dang, Weiwei. “The Controversial World of Sirtuins.” Drug discovery today. Technologies 12 (2014): e9–e17. PMC. Web. 1 Dec. 2017. Link.


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