The COVID-19 pandemic may be over, but our immune systems are still feeling the impact. After years of battling constant viral threats, from COVID-19 to seasonal flu and other infections, our body’s defense system is exhausted. Many people continue to experience lingering inflammation, frequent illnesses, and slower recovery times. This extended state of immune stress has compromised us further to chronic illness, including autoimmune diseases and even neurodegenerative diseases such as Parkinson's. So why is our immune system still in trouble? And how do we give it its power back? Understanding immune exhaustion is the beginning of rebuilding our body's natural immunity.

A weakened immune system makes people more susceptible to disease, mental illnesses, and even sleep disorders. Now, new research indicates that immune system depletion may play an important role in the onset of Parkinson's disease, a degenerative neurologic disorder that compromises movement and cognition.

Role of Inflammation in Parkinson's Disease

Dysfunctional immune response is a leading cause of long-standing inflammation within the body, that has been found to contribute towards a multitude of conditions, including cardiovascular conditions, diabetes, depression, and neurodegenerative diseases such as Alzheimer's.

As people age, their immune system naturally becomes less effective. This deterioration, referred to as immune exhaustion, may be a key contributor to the onset and progression of Parkinson’s disease. Rebecca Wallings, a Parkinson’s Foundation Launch Award grant recipient and senior postdoctoral fellow at the University of Florida, believes that an accumulation of exhausted immune cells could be driving neurodegeneration in Parkinson’s patients.

How a Tired Immune System Might Affect Parkinson's?

Parkinson's disease is most commonly linked with the degeneration and loss of dopaminergic neurons—motor nerve cells that produce dopamine, an essential neurotransmitter for movement. While researchers have long suspected inflammation is involved in this neurodegeneration, the mechanisms are not yet well understood.

Wallings' study is on immune cell exhaustion, a process by which aging immune cells fail to control immune responses effectively. Her research indicates that instead of dampening inflammation in Parkinson's patients, attempts should be made to rejuvenate the immune system to regain its functionality.

Energy Deficiency in Immune Cells

One of the major findings of Wallings' work is the function of mitochondrial impairment in immune cell exhaustion. Mitochondria are commonly called the powerhouses of cells, as they are vital for generating energy. As mitochondria age and become inefficient, immune cells fail to function well, potentially accelerating neurodegeneration in Parkinson's disease.

Wallings has found that mutations in the LRRK2 gene, a recognized genetic risk factor for Parkinson's disease, are linked with defective mitochondrial function and immune cell exhaustion. Her current work includes testing various therapeutic approaches to restore mitochondrial function in immune cells with the potential to enhance the immune system and potentially prevent or treat Parkinson's disease.

Will Rejuvenating the Immune System Help in Treatment?

For decades, the standard practice in treating Parkinson's has been to suppress brain inflammation. Yet Wallings' work indicates that instead of slowing down immune responses, restoring the immune system could be a more successful strategy. By addressing mitochondrial impairment and immune resilience, researchers can potentially reverse or slow down Parkinson's disease.

Wallings is now looking into how to rejuvenate immune cells by fixing mitochondria. She studies immune cells from patients with Parkinson's as well as from healthy subjects and performs experiments on animal models to determine if rejuvenation of the immune system could result in improved disease outcomes.

Lifestyle Factors That May Affect Parkinson's Risk

While there is no cure for Parkinson's disease, some lifestyle adjustments may decrease the chances of developing the illness. Since neurodegenerative diseases are associated with chronic inflammation and immune dysfunction, developing habits that enhance immune function might prove helpful.

Diet: There is evidence to suggest that eating in accordance with the Mediterranean or MIND diets, both high in antioxidants, healthy fats, and anti-inflammatory foods, can encourage brain wellness and reduce Parkinson's risk.

Avoiding Dangerous Substances: Restricting alcohol and nicotine use can maintain a robust immune system and suppress inflammation.

Reducing Stress: Chronic stress weakens immune function, so methods such as meditation, exercise, and sufficient sleep can lead to improved overall well-being.

The liver and heart are two of the most vital organs of the body, and although they perform very different functions, they are closely connected. When the liver is not functioning properly, it can place significant stress on the heart and circulatory system of the body.

Liver disease not only affects the digestion process, metabolism, and detoxification but can also trigger serious cardiovascular changes that may go unnoticed in the early stages. Understanding this particular connection is significant for timely diagnosis and better overall care.

The Liver-Heart Connection

The liver helps to regulate the flow of blood, fluid balance, cholesterol metabolism, and inflammation as well. When liver disease develops—whether due to fatty liver, hepatitis, cirrhosis, or alcohol-related damage—all these processes become disturbed.

As a result of the same, the heart may have to work harder to maintain circulation, while blood vessels may also undergo certain changes that impact blood pressure and delivery of oxygen as well.

Changes In Blood Circulation

In well-advanced liver disease, especially cirrhosis, the flow of blood through the liver becomes restricted. This can also increase pressure in the portal vein, a condition known as portal hypertension. At the same point in time, blood vessels in the rest of the body may also widen, causing a drop in effective blood pressure.

To compensate, the heart pumps faster and harder. With the passage of time, this constant strain can weaken cardiac function and even lead to a condition sometimes referred to as cirrhotic cardiomyopathy, where the heart does not respond normally under stress.

Fluid Retention And Heart Stress

Liver disease often causes the body to retain both salt and water. This can also lead to swelling in the legs, abdomen, and surrounding tissues as well. Extra fluid in the body increases the workload on the heart, making it more difficult for it to pump blood in an efficient way. In severe cases, this may also contribute to shortness of breath, fatigue, and worsening cardiovascular strain.

Inflammation And Metabolic Impact

Some of the conditions, such as non-alcoholic fatty liver disease, are also linked with diabetes, obesity, high levels of cholesterol, and high blood pressure – all of which are the major risk factors for heart disease. Chronic inflammation, well-associated with liver damage, may further increase the risk of atherosclerosis and other cardiac complications.

GLP-1 receptor agonist drugs such as Ozempic and Wegovy have shown significant benefits for people with diabetes and obesity. However, not everyone experiences the same results.

Now, a study suggests that this variation may be due to genetic resistance, which means that some people are biologically less responsive to these medications, making these drugs less effective.

Also Read: NAFLD to MASLD: Experts Explain Why This Common Yet Dangerous Liver Condition Got Renamed

The new study by scientists at Stanford University in the US showed that about 10 per cent of the general population carry genetic variants that lead to what the researchers called “GLP-1 resistance”.

The GLP-1- receptor agonist drugs typically work by mimicking the hormone GLP-1 (glucagon-like peptide-1), which naturally helps regulate blood sugar by stimulating insulin release. The process slows the emptying of the stomach and reduces appetite.

However, in individuals with certain genetic variants, the team found that higher levels of GLP-1 did not regulate blood sugar better.

The researchers noted that the findings, published in the journal Genome Medicine, may be key to developing new therapies for people with GLP-1 resistance.

“There are a whole class of medications that are insulin sensitizers, so perhaps we can develop medications that will allow people to be sensitized to GLP-1s or find formulations of GLP-1, like the longer-acting versions, that avoid the GLP-1 resistance,” said Anna Gloyn, professor of pediatrics and of genetics at Stanford Medicine.

The Gene Linked to GLP-1 Resistance

Also read: Foundayo: US FDA Approves Eli Lilly’s GLP-1 Weight Loss Pill

To zero in on the gene resistant to GLP-1 drugs, the team conducted experiments in humans. They traced this resistance to a PAM variant known as p.S539W.

PAM (peptidyl-glycine alpha-amidating monooxygenase) is an enzyme that is uniquely capable of activating many hormones in the body, including GLP-1.

While the researchers suspected that people with the PAM variant would have lower levels of GLP-1 in their blood, it actually increased levels of GLP-1. Although the exact mechanism is still unclear, experiments in both humans and mice confirmed signs of reduced response to GLP-1.

Analyzing diabetes drug trial data, they found that individuals with these variants were less able to lower their blood sugar levels even after six months of treatment. This suggests that despite having more circulating GLP-1, their bodies are less responsive to it.

“When I treat patients in the diabetes clinic, I see a huge variation in response to these GLP-1-based medications and it is difficult to predict this response clinically,” said Mahesh Umapathysivam, an endocrinologist and clinical researcher at Adelaide University in Australia.

“This is the first step in being able to use someone’s genetic make-up to help us improve that decision-making process,” he added.

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Importantly, participants with the PAM variants did not respond differently to other common diabetes treatments, including sulfonylureas, metformin, and DPP-4i.

The finding may help develop precision medicine, the researchers said. Knowing ahead of time who is likely to respond would help patients get on the right drugs faster, Gloyn said.

Reasons Why Ozempic May Not Help All People Lose Weight

Ozempic is primarily indicated for type 2 diabetes management. But some doctors may prescribe it for weight loss in appropriate patients without diabetes.

Previous research has shown that medical conditions such as sleep apnea, along with certain common medications, such as antidepressants, steroids, and contraceptives, can hamper the process of shedding extra pounds.

Another major reason that can hamper weight loss is the side-effects of these drugs that can prompt a person to halt their prescription mid-way.

Once widely known as non-alcoholic fatty liver disease (NAFLD), the common and dangerous fatty liver condition was rephrased as Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) due to its strong link to metabolic health issues like obesity and diabetes.

MASLD now includes patients with fatty liver disease linked to metabolic risk factors such as obesity, diabetes, and hypertension.

Also Read: GLP-1 Drugs: Why Not Everyone Taking Ozempic May Have Lower Blood Sugar Levels

MASLD: So What Prompted The Change?

Globally, it was observed that all patients who have non-alcoholic fatty liver disease also have some associated form of metabolic dysfunction. The patients reported having either obesity, diabetes, metabolic syndrome, hypertension, or cholesterol problems.

And all these problems eventually lead to significant comorbidities later, like some people developed heart disease, while others developed complications of diabetes.

In view of these, a global consensus process in 2023 involving hundreds of experts from different countries adopted MASLD as it better reflected these underlying causes of the condition.

What Does MASLD Mean?

Also read: Lancet Study Shows Metabolic Liver Disease To Rise Over 38% By 2050: What’s Behind The Surge

MASLD is an umbrella term for liver conditions that develop in the presence of 1 or more cardiometabolic risk factors—including high blood sugar, elevated body mass index (BMI), and hypertension—but in the absence of other causes of liver fat accumulation.

The condition can be defined by excess liver fat accumulation (more than 5 per cent of liver weight) in the presence of metabolic dysfunction, independent of alcohol intake.

It encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma.

“Initially, it was thought that having fatty liver disease without alcohol was a benign condition, but now it is recognized that, since it is associated with lots of metabolic comorbidities, it's no longer benign,” Dr. Ashish Kumar, Professor of gastroenterology and hepatology at Sir Ganga Ram Hospital in New Delhi, told HealthandMe.

He stated that whenever a diagnosis of fatty liver is present, "we should actually include other comorbidities, like obesity, dyslipidemia, which means cholesterol problem, diabetes, sugar problem, pre-diabetes, and hypertension. At least 50–70–80 percent of these patients will have one or more of these comorbidities".

Why Alcohol Is Not The Only Culprit For Fatty Liver

Although alcohol has remained the number one risk for liver disease, MASLD seems to be rising globally, including among people who do not drink. Why?

The reasons include:

a sedentary lifestyle,

increased consumption of fast and processed food,

lack of exercise,

lack of sleep,

stressful life.

Also read: Why Regular Scans Are Crucial for Liver Cancer Patients: Doctors Explain

The experts noted that food, especially the increasingly accessible junk food or processed food, is a major culprit.

“So even if the person is not drinking alcohol, people are developing addiction to processed food, and this is causing an epidemic level of obesity and diabetes. Consequently, MASLD is also increasing, and now it is becoming the number one cause of liver disease,” Dr Kumar said.

How To Prevent MASLD?

According to Dr. Sanjay Goja, Director, Liver Transplant & HPB Surgery, Narayana Hospital, Gurugram, prevention must focus on following a healthy lifestyle like maintaining a healthy BMI, engaging in regular physical activity, and eating a balanced diet.

Controlling diabetes, cholesterol, and blood pressure is also important to prevent the risk of MASLD.

Dr Siddharth Badola, Manipal Hospital, Ghaziabad, suggested sustainable lifestyle changes such as:

Maintaining an adequate body weight: Even slight weight loss (5–10 percent) has been shown to significantly reduce liver fat and inflammation.

Follow a balanced and nutrient-rich diet: People should focus on consuming whole grains, fresh fruits and vegetables, lean proteins, and healthy fats, while limiting refined carbohydrates and processed foods.

Avoid foods with added sugar: Excess consumption of fructose, commonly found in packaged foods and sugary beverages, is a key contributor to fat accumulation in the liver.

Engage in regular physical activity: At least 150 minutes of moderate-intensity exercise per week is recommended to improve insulin sensitivity and liver health.

Manage associated metabolic conditions: Effective control of diabetes, hypertension, and dyslipidemia is essential in reducing the risk of MASLD progression.

Ensure adequate sleep and stress management: Poor sleep quality and chronic stress can negatively impact metabolic balance and liver function.

Keep your body hydrated with ample water intake and follow structured meal timings.