Obesity and amyotrophic lateral sclerosis (ALS) are two complex diseases that have garnered much interest in recent years due to rising prevalence rates and the significant morbidity and mortality associated with both conditions. Obesity is characterized by excessive body fat accumulation that impairs health, while ALS is a progressive neurodegenerative disease affecting motor neurons in the brain and spinal cord, ultimately leading to paralysis and death typically within 2-5 years of diagnosis.
The potential link between obesity and ALS is compelling given the overlapping risk factors and pathophysiology between the two conditions. However, the nature of the relationship remains unclear. Some key questions that need to be addressed include:
Is there an association between obesity and risk of developing ALS?
Multiple large cohort studies have found that obesity in early adulthood or mid-life is associated with a higher future risk of ALS. For example, a pooled analysis of over 5 million people found that being obese at age 20-49 years was linked to a 33% higher risk of ALS later in life. However, other studies have not found a significant association, so more research is needed to clarify if obesity is an independent risk factor for ALS.
Does obesity influence the progression and severity of ALS?
Some studies indicate that obesity leads to more rapid progression of ALS symptoms and shorter survival times after diagnosis. This may be related to increased inflammation, higher calorie needs, and reduced mobility associated with excess weight. However, other studies have found no relationship between BMI and ALS progression. Additional well-controlled studies are required to determine if managing obesity could slow the advancement of ALS.
Are there common biological mechanisms between obesity and ALS pathogenesis?
Emerging research suggests obesity and ALS may share similar pathophysiological changes, including increased systemic inflammation, oxidative stress, insulin resistance, and mitochondrial dysfunction. Fat tissue is metabolically active and can secrete inflammatory factors and adipokines that may contribute to neurodegeneration. Understanding common mechanisms may unveil new treatment targets for ALS.
Could treatments for obesity affect the course of ALS?
Lifestyle interventions targeting obesity such as diet, exercise, and bariatric surgery may have beneficial effects on the progression of ALS according to some preliminary studies. For example, reduced calorie intake has been shown to promote neuronal survival in ALS mouse models. However, human studies are lacking, and excess weight loss could also worsen outcomes in ALS. More research is required to determine if obesity-directed therapies could also slow the disease course in ALS patients.
Obesity Statistics and Trends
The prevalence of obesity has increased dramatically worldwide over the past several decades. Some key statistics on obesity rates include:
| In the United States | Over 40% of adults are obese, with 35% being overweight |
| Global estimates | In 2016, approximately 13% of the world’s adult population (11% of men and 15% of women) were obese |
| Childhood obesity | In the US, obesity affects around 19% of children and adolescents |
| Future projections | Global obesity prevalence is projected to reach 20% by 2025 |
This rising propensity for excessive adiposity is concerning given the myriad of adverse health consequences associated with obesity, including type 2 diabetes, cardiovascular disease, cancer, osteoarthritis, and neurological conditions like ALS. The causes of escalating obesity rates are multifactorial, involving genetic, lifestyle, and environmental influences.
ALS Epidemiology
ALS is a rare, debilitating neurodegenerative disorder. Key epidemiological characteristics of ALS include:
| Prevalence | 3-5 per 100,000 globally |
| Incidence | Approximately 2 per 100,000 people newly develop ALS each year |
| Peak age of onset | 55-75 years old, average around 60 years |
| Gender | Slightly more common in men than women |
| Survival | Average 2-5 years after symptom onset |
| Causes | Largely unknown, probably involves gene-environment interactions |
ALS causes relentless, progressive paralysis and typically results in death due to respiratory failure. Only two FDA-approved drugs are available that modestly slow disease progression. Given the poor prognosis, research aimed at understanding potentially modifiable ALS risk factors like obesity is imperative.
Possible Biological Links Between Obesity and ALS
Obesity and ALS appear to share several key pathophysiological changes that may mechanistically connect the two conditions:
Chronic Inflammation
Adipose tissue secretes pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Obese individuals have chronically elevated levels of these factors, which can activate inflammatory pathways in the brain and spinal cord. Neuroinflammation is increasingly recognized as a contributor to ALS progression.
Oxidative Stress
Obesity can induce systemic oxidative stress, which is an imbalance between free radical production and antioxidant defenses. Oxidative damage to lipids, proteins, and DNA is implicated in ALS pathology.
Insulin Resistance
Obesity markedly increases the risk of insulin resistance and type 2 diabetes. Insulin dysfunction and impaired glucose tolerance are linked to more rapidly progressing ALS. Restoring insulin sensitivity may be neuroprotective.
Mitochondrial Dysfunction
Excess nutrients and lipids can impair mitochondrial function. Mitochondrial abnormalities occur in ALS motor neurons. Improving mitochondrial health may benefit both obesity and ALS.
Adipokines and Neurotrophic Factors
Adipose tissue secretes adipokines like leptin, which regulate appetite and metabolism. Altered circulating adipokine levels associated with obesity may impact nervous system health. Neurotrophic factors that support neuron survival and growth are also disrupted with obesity.
Potential Mechanisms Linking Obesity and ALS
Several biological mechanisms have been proposed that could directly link obesity with increased risk and severity of ALS:
Adipose-Derived Inflammation
Adipose tissue produces pro-inflammatory cytokines itself in obesity, which can enter the CNS and drive neuroinflammation, a contributor to neurodegeneration.
Leaky Gut and Systemic Inflammation
Obesity is associated with increased intestinal permeability, allowing bacteria and endotoxins to escape into circulation and activate widespread inflammation, which may promote CNS inflammation.
Dyslipidemia and Cerebrovascular Dysfunction
Obesity alters blood cholesterol levels and triggers vascular disease. Dyslipidemia and altered perfusion may damage motor neuron health.
Impaired Blood-Brain-Barrier Integrity
Disruption of the blood-brain barrier associated with obesity may allow passage of toxic molecules, cytokines, and lipids into the CNS that can cause neuronal damage.
Insulin Resistance and Neuronal Dysfunction
Impaired insulin signaling with obesity can directly promote CNS inflammation and reduce neuroprotective effects of insulin on motor neurons.
Mitochondrial Dysfunction and Bioenergetics
Nutrient excess and lipid accumulation impairs mitochondrial function systemically and in the CNS, which may energetically starve motor neurons and impair survival pathways.
Evidence from Epidemiological Studies on Obesity and ALS Risk
A number of large prospective cohort studies have investigated the association between obesity and future ALS risk:
| Study | Main Findings |
| Pooled analysis of 5 cohort studies (N>5 million) | Obesity at age 20-49 associated with 33% higher ALS risk |
| National Institutes of Health-AARP cohort (N>900,000) | Obese individuals had 56% higher ALS risk vs normal weight |
| Cancer Prevention Study-II Nutrition Cohort | ALS risk increased in early adulthood obesity but not midlife |
| Swedish AMORIS study (N>500,000) | Overweight and obesity linked to higher ALS risk |
These studies provide evidence that obesity, particularly in early adulthood and middle age, is associated with greater odds of subsequently developing ALS. Some studies have not found significant links between elevated BMI and ALS, so further research is still needed.
Obesity and ALS Progression and Outcomes
Emerging data also indicates that obese ALS patients may experience more rapid progression of weakness and shorter survival:
| Study | Main Findings |
| University of Michigan ALS clinic | Obese ALS patients had faster disease progression |
| Italian multicenter study | Higher BMI associated with shorter survival in ALS |
| Emory ALS clinic study | No association between BMI and disease progression found |
The relationship between obesity and survival in ALS remains unclear. Some studies show no association between BMI and survival. Addressing reverse causality is also important, as weight loss often occurs with ALS progression due to malnutrition. Further high-quality research is required to determine if controlling obesity improves ALS outcomes.
Potential Role of Weight Loss and Metabolic Interventions in ALS
Given the links between obesity and ALS risk and progression, interventions targeting weight management could hypothetically impact ALS outcomes:
Caloric restriction
Reducing caloric intake has extended lifespan and protected neurons in animal models. Whether dietary restriction and fasting regimens can safely slow ALS progression requires study.
Bariatric surgery
Weight loss surgery such as gastric bypass or banding can dramatically reduce body weight and improve metabolic factors. Case reports indicate bariatric surgery stabilized or improved ALS in some patients.
Ketogenic diet
Ketogenic, very low-carbohydrate diets can promote weight loss and ketone-based metabolism. Ketones may provide an alternative neuronal energy source in ALS. Small trials are underway.
Exercise
Physical activity supports weight management and improves metabolic factors like insulin sensitivity. Early research suggests exercise may slow ALS progression, but excess fatigue is a concern.
Overall, interventions that address obesity and related metabolic dysfunction hold promise for impacting the ALS disease course, but clinical trials are still needed.
Conclusion
In summary, epidemiological evidence suggests obesity, particularly in early adulthood, is associated with an increased risk of developing ALS later in life. Obesity also appears linked to more rapidly progressing ALS and shorter survival in some studies. Several biological mechanisms may help explain potential causal relationships between obesity and ALS onset and severity, including chronic inflammation, insulin resistance, and mitochondrial dysfunction. Research into weight management and metabolic approaches for improving ALS outcomes shows preliminary promise but larger clinical trials are still lacking. While many questions remain unresolved, the existing evidence underscores the need to further investigate the intersection between obesity and ALS in the hopes of uncovering new therapeutic targets.