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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


Using Frogs to Tackle Kidney Problems

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Cilia

Credit: Vanja Krneta-Stankic and Rachel K. Miller, University of Texas Health Science Center at Houston

Many human cells are adorned with hair-like projections called cilia. Scientists now realize that these specialized structures play many important roles throughout the body, including directing or sensing various signals such as fluid flow. Their improper function has been linked to a wide range of health conditions, such as kidney disease, scoliosis, and obesity.

Studying cilia in people can be pretty challenging. It’s less tricky in a commonly used model organism: Xenopus laevis, or the African clawed frog. This image highlights a healthy patch of motile cilia (yellow) on embryonic skin cells (red) of Xenopus laevis. The cilia found in humans and all other vertebrates are built from essentially the same elongated structures known as microtubules. That’s why researchers can learn a lot about human cilia by studying frogs.


Poor Sleep Habits in Adolescence Correlated with Cardiovascular Risk

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Stressed by schoolwork

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Just ask any parent or teacher, most of today’s teens and pre-teens don’t seem to get enough sleep. And what sleep they do get is often poor quality—no great surprise, given that smartphones and other electronic devices are usually never far from their reach. Now, an NIH-funded team has uncovered the strongest evidence yet that this lack of quality sleep may be setting our kids up for some serious health issues later in life.

The team’s study of more than 800 adolescents, ages 11 through 13, confirmed that many are getting an insufficient amount of undisturbed, restful sleep each night. While earlier studies had found a link between sleep duration and obesity [1], the new work shows that a wide range of other cardiovascular risk factors are affected by both too little sleep and poor sleep quality [2]. When compared to well-rested kids, sleep-deprived youth were found to have higher blood pressure, bigger waistlines, and lower levels of high density lipoprotein (HDL) cholesterol, which is associated with lower risk of cardiovascular disease.


Does Gastric Bypass Reduce Cardiovascular Complications of Diabetes?

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Doctor with patient

Thinkstock/IPGGutenbergUKLtd

For obese people with diabetes, doctors have increasingly been offering gastric bypass surgery as a way to lose weight and control blood glucose levels. Short-term results are often impressive, but questions have remained about the long-term benefits of such operations. Now, a large, international study has some answers.

Soon after gastric bypass surgery, about 50 percent of folks not only lost weight but they also showed well-controlled blood glucose, cholesterol, and blood pressure. The good news is that five years later about half of those who originally showed those broad benefits of surgery maintained that healthy profile. The not-so-good news is that the other half, while they generally continued to sustain weight loss and better glucose control, began to show signs of increasing risk for cardiovascular complications.


Unraveling the Biocircuitry of Obesity

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Mouse neurons

Caption: Mouse neurons (purple), with their nuclei (blue) and primary cilia (green).
Credit: Yi Wang, Vaisse Lab, UCSF

Obesity involves the complex interplay of diet, lifestyle, genetics, and even the bacteria living in the gut. But there are other less-appreciated factors that are likely involved, and a new NIH-supported study suggests one that you probably never would have imagined: antenna-like sensory projections on brain cells.

The study in mice, published in the journal Nature Genetics [1], suggests these neuronal projections, called primary cilia, are a key part of a known “hunger circuit,” which receives signals from other parts of the body to control appetite. The researchers add important evidence in mouse studies showing that changes in the primary cilia can produce a short circuit, impairing the brain’s ability to regulate appetite and leading to overeating and obesity.


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