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Connecting Senescent Cells to Obesity and Anxiety

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Graphical Abstract
Adapted from Ogrodnik et al., 2019, Cell Metabolism.

Obesity—which affects about 4 in 10 U.S. adults—increases the risk for lots of human health problems: diabetes, heart disease, certain cancers, and even anxiety and depression [1]. It’s also been associated with increased accumulation of senescent cells, which are older cells that resist death even as they lose the ability to grow and divide.

Now, NIH-funded researchers have found that when lean mice are fed a high-fat diet that makes them obese, they also have more senescent cells in their brain and show more anxious behaviors [2]. The researchers could reduce this obesity-driven anxiety using so-called senolytic drugs that cleared away the senescent cells. These findings are among the first to provide proof-of-concept that senolytics may offer a new avenue for treating an array of neuropsychiatric disorders, in addition to many other chronic conditions.

As we age, senescent cells accumulate in many parts of the body [3]. But cells can also enter a senescent state at any point in life in response to major stresses, such as DNA damage or chronic infection. Studies suggest that having lots of senescent cells around, especially later in life, is associated with a wide variety of chronic conditions, including osteoporosis, osteoarthritis, vascular disease, and general frailty.

Senescent cells display a “zombie”-like behavior known as a senescence-associated secretory phenotype (SASP). In this death-defying, zombie-like state, the cells ramp up their release of proteins, bioactive lipids, DNA, and other factors that, like a zombie virus, induce nearby healthy cells to join in the dysfunction.

In fact, the team behind this latest study, led by James Kirkland, Mayo Clinic, Rochester, MN, recently showed that transplanting small numbers of senescent cells into young mice is enough to cause them weakness, frailty, and persistent health problems. Those ill effects were alleviated with a senolytic cocktail, including dasatinib (a leukemia drug) and quercetin (a plant compound). This drug cocktail overrode the zombie-like SASP phenotype and forced the senescent cells to undergo programmed cell death and finally die.

Previous research indicates that senescent cells also accumulate in obesity, and not just in adipose tissues. Moreover, recent studies have linked senescent cells in the brain to neurodegenerative conditions, including Alzheimer’s disease, and showed in mice that dasatinib and quercetin helps to alleviate neurodegenerative disease [4,5]. In the latest paper, published in the journal Cell Metabolism, Kirkland and colleagues asked whether senescent cells in the brain also could explain anxiety-like behavior in obesity.

The answer appears to be “yes.” The researchers showed that lean mice, if allowed to feast on a high-fat diet, grew obese and became more anxious about exploring open spaces and elevated mazes.

The researchers also found that the obese mice had an increase in senescent cells in the white matter near the lateral ventricle, a part of the brain that offers a pathway for cerebrospinal fluid. Those senescent cells also contained an excessive amount of fat. Could senolytic drugs clear those cells and make the obesity-related anxiety go away?

To find out, the researchers treated lean and obese mice with a senolytic drug for 10 weeks. The treatment didn’t lead to any changes in body weight. But, as senescent cells were cleared from their brains, the obese mice showed a significant reduction in their anxiety-related behavior. They lost their anxiety without losing the weight!

More preclinical study is needed to understand more precisely how the treatment works. But, it’s worth noting that clinical trials testing a variety of senolytic drugs are already underway for many conditions associated with senescent cells, including chronic kidney disease [6,7], frailty [8], and premature aging associated with bone marrow transplant [9].

As a matter of fact, just after the Cell Metabolism paper came out, Kirkland’s team published encouraging though preliminary, first-in-human results of the previously mentioned senolytic drug dasatinib in 14 people with age-related idiopathic pulmonary fibrosis, a condition in which lung tissue becomes damaged and scarred [10]. Caution is warranted as we learn more about the associated risks and benefits, but it’s safe to say we’ll be hearing a lot more about senolytics in the years ahead.

References:

[1] Adult obesity facts (Centers for Disease Control and Prevention)

[2] Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Ogrodnik M et al. Cell Metabolism. 2019 Jan 3.

[3] Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies. Tchkonia T, Kirkland JL. JAMA. 2018 Oct 2;320(13):1319-1320.

[4] Tau protein aggregation is associated with cellular senescence in the brain. Musi N, Valentine JM, Sickora KR, Baeuerle E, Thompson CS, Shen Q, Orr ME. Aging Cell. 2018 Dec;17(6):e12840.

[5] Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ. Nature. 2018 Oct;562(7728):578-582.

[6] Inflammation and Stem Cells in Diabetic and Chronic Kidney Disease. ClinicalTrials.gov, Sep 2018.

[7] Senescence in Chronic Kidney Disease. Clinicaltrials.gov, Sep 2018.

[8] Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Adults (AFFIRM-LITE). Clinicaltrials.gov, Dec 2018.

[9] Hematopoietic Stem Cell Transplant Survivors Study (HTSS Study). Clinicaltrials.gov, Sep 2018.

[10] Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. Justice JN, Nambiar AN, Tchkonia T, LeBrasseur K, Pascual R, Hashmi SK, Prata L, Masternak MM, Kritchevsky SB, Musi N, Kirkland JL. EBioMed. 5 Jan. 2019. [Epub ahead of print]

Links:

Healthy Aging (National Institute on Aging/NIH)

Video: Vail Scientific Summit James Kirkland Interview (Youtube)

James Kirkland (Mayo Clinic, Rochester, MN)

NIH Support: National Institute on Aging; National Institute of Neurological Disorders and Stroke

8 Comments

  • Connie Mattingly says:

    It is so sad to watch a loved one live with so many anxieties. Wonderful to see they’re working towards a plan.

  • MARK RUSSELL says:

    Psychology became a Science at the “Boulder Conference” in 1946. These findings could change the whole Psychology /Psychiatry Model. We have an Epidemic in Mega Stress (PTSD, Television Stress, Radio Stress, Work Stress, Family Stress, Lost Job, Divorce, Bankruptcy, Aging, and Life Stress). What if we could reduce 30–50% of all Stress with these finding? What if a Bad Marriages could be repaired and what if we could rebuild a Mother Daughter Relationship? A Stressed/Anxiety Person can affect the whole community and many times there is great damage. A Wheel functions optimally at –0– Stress. The question we want to ask is——How much Stress/Anxiety can the Synolytic Drugs Reduce? Anti-Biotics were release in 1942 and in the early 1800’s we had the first Stethoscope. We went to the MMMMoon in 1969 and our Cell Phones have over 10 times more power then the Computer that went to the Moon.

  • Lisa Kavanaugh says:

    This study leaves me wondering, what type of fat were these mice fed? Any fat? Fat from factory farm animals? Fat from seed/nuts? Fat from organic sources? What were the controls in the type of fat used? As a person who consumes an ample amount of fat from organic coconut, avocado, and raw, organic milk, I’ve never suffered from obesity or high cholesterol. Prior to removing non-organic, processed foods from my diet, I was about 10 lbs. overweight and had higher cholesterol numbers. I actually eat more fat in my diet now (the above mentioned) than I did then. I do not believe it is the fat that’s causing obesity and would like more info on this study because it is misleading. Processed foods, low-fat foods contain higher carbohydrates, which are turned into fat – not the good kind. Please explain.

    • Erin M. Bank says:

      I wondered a similar thing (if the type of fat mattered), and went down a little bit of a rabbit (mouse?) hole: I looked to the methods section of the primary paper (reference #2 above): “High fat food was purchased from Research Diets (cat no #D12492). 60% of calories in this high fat diet are from fat. Standard mouse chow diet was obtained from Lab Diet (cat no #5053).” If you go further, you can find the ingredients of the chow at https://researchdiets.com/formulas/d12492 and learn the fat sources are “lard” and “soybean oil.” No nuts or avocados to be found – I agree it would be interested to know if the type of fat that could have these effects. Obviously, there are limitations to a chow diet, so they won’t really mimic the fat sources we have a choice between as humans. But you’re probably not eating 60% of your diet from fat.

  • Toni says:

    Great news. I have suffered from anxiety although not obese, my anxiety got really bad living in mold.

  • Pratap Blr says:

    It’s wonder that DNA maybe a damaged, as you said “such as DNA damage or chronic infection. Studies suggest that having lots of senescent cells around, especially later in life, is associated”. thank god we are programmed and only programming is running in out blood. Thanks.

  • SMLEQB says:

    Well, obesity is surely one of the most concerned issue these days and we need more studies in order to get rid of this nuisance.

  • Kathy says:

    What type of Doctor could help one w this condition get well.

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