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Exercise and Clinical Immunology > Aging and hospitalization - L9 > Flashcards

Aging and hospitalization - L9 Flashcards

1
Q

Name hallmarks of aging.

A
  • Loss of proteostasis
  • Epigenetic alterations
  • Telomere attrition
  • Genomic instability
  • Altered intracellular communication
  • Stem cell exhaustion
  • Cellular senescence
  • Mitochondrial dysfunction
  • Dysregulated nutrient sensing
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2
Q

What is sarcopenia?

A

The age-related loss of muscle mass and function (strength)

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3
Q

What is the difference between primary sarcopenia and secondary sarcopenia?

A
  • Primary sarcopenia is due to aging
  • Secondary sarcopenia is due to inactivity, malnutrition, or illness-related.
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4
Q

Describe in short the pathophysiology of sarcopenia.

A
  • Lifestyle changes such as decreased physical activity lead to hormonal changes.
  • Hormonal changes such as the decrease in sex hormones lead to sarcopenia.
  • Lifestyle changes such as decreased physical activity also lead to decreased fibre size and amount of satellite cells.
  • Inflammation indirectly leads to sarcopenia by influencing fibre size and amounto of satellite cells and by influencing the amount of motor units and fiber numbers.
  • Motorneuron death indirectly leads to sarcopenia by decreasing the amount of motor units and fiber numbers, which lead to sarcopenia.
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5
Q

Age determines muscle size. What can be an explanation of this?

A

More inflammatory cytokines in aging (inflammaging).

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6
Q

What inflammatory markers have been found to be associated with aging?

A
  • TNF-a expression is higher in muscles from elderly people.
  • Higher IL-6 and CRP are associated with poorer physical performance and poorer cognitive performance.
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7
Q

What is immunosenescence?

A

Remodelling of the immune system with age, where there is loss of immune functions leading to a decline in immunity.

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8
Q

Name consequences of immunosenescence.

A
  • Lower lymphocyte number responding to new antigens
  • T cell response to antigens slowed down
  • Macrophages destroy bacteria, cancer cells and other antigens less quickly (possibly contributing to increased incidence of cancer among elderly)
  • Complement system produces less plasma proteins in response to bacterial infections
  • Immune system becomes less able to distinguish self from nonself, making auto-immune disorders more common
  • Less antibodies produced in response to antigen
  • Antibodies are less efficient in binding to antigens.
  • Vaccines less effective
  • Higher risk and incidence of disease such as pneumonia and influenza
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9
Q

Describe the effect of immunosenescence on the function of the following immune cells:

  • T lymphocytes
  • B lymphocytes
  • Macrophages
  • Mast cells
  • NK cells
  • Neutrophils
A
  • T lymphocytes: increased memore CD8+ T cells and decreased naive CD4+ T cells
  • B lymphocytes: decreased B-cell production
  • Macrophages: decreased phagocytosis and increased inflammatory cytokine production
  • Mast cells: decreased mast cell production and increased mast cell degranulation
  • NK cells: decreased cytotoxicity and IL-2 production
  • Neutrophils: decreased chemotaxis, free radical production and apoptosis
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10
Q

Context information:

  • 30% of elderly experience at least one fall yearly
  • 10% of falls result in fracture
  • 1% of falls result in hip fractures
  • Increased mortality
  • Risk factor for falls: lower extremity weakness
A
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11
Q

What is associated with NLRP3 inflammasome activation?

A

Metabolic and morphological alterations in skeletal muscle

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12
Q
  • What is the relationship between NLRP3 and LPS?
  • What is the relationship between IL-1β and LPS?
A
  • NLRP3 activation responds in a dose-dependent manner to LPS. The more LPS (i.e. inflammation), the more NLRP3 is activated.
  • Since IL-1β is produced as a result of NLRP3 activation and subsequent production of caspase-1 that cleaves pro-IL-1β into IL-1β, IL1β can be linked to exposure of LPS.
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13
Q

What relationship exists between myotube diameter and LPS levels?

A
  • 0 ng/ml LPS is associated with an increasing myotube diameters, whereas 100 ng/ml LPS is associated with a reduced increase in myotube diameter.
  • When LPS is combined with a pharmacological inhibitor of NLRP3‐induced IL‐1β production (MCC950), this leads to an average increase in myotube diameter. Suggesting that IL-1β is crucial in the morphological and metabolic changes in skeletal muscle upon NLRP3 inflammasome activation.
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14
Q

What association exists between NLRP3 and mitochondria?

A

A study used immunostaining for SDHA (subunit of mitochondrial complex II) and NLRP3 to identify mitochondrial localization of LRP3 in vehicle-treated myotubes. Upon LPS exposure, more NLRP3 associated with mitochondria, shown by increasing colocalization between NLRP3 and SDHA.

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15
Q

What happened to oxygen consumption and acidification rate (glycolytic rates) (measures of mitochondrial metabolism) in myotubes exposed to LPS?

A

Exposure to LPS resulted in a higher oxygen consumption and a higher acidification rate.

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16
Q

What happens to mitochondrial morphology after LPS exposure in myotubes?

A

Myotube exposure to LPS significantly decreased mitochondrial size and increase in circularity upon LPS exposure.

17
Q

What evidence is there regarding the presence of inflammation in myotubes exposed by LPS?

A

LPS exposure to myotubes is associated with an increase in mtROS production.

mtROS production was mitigated by the addition of the pharmacological inhibitor of NLRP3‐induced IL‐1β production (MCC950)

18
Q

What is a major hazard of hospitalization?

A

Periods of inactivity leading to a accelerated rate of skeletal muscle atrophy (1 kg muscle mass loss in 10 days hospitalized).

19
Q

The bedrest study by NASA and ESA 2019 investigated the influence of bed rest on skeletal muscle for up to 55 days. Three measurements over time were performed, where blood was drawn and a muscle biopsy was performed.
What findings were found when investigating the muscle biopsies of these participants?

A
  • Broken myofibrils
  • Glycogen and fat accumulation
  • Presence of lysosomes
  • Distrubed structure of myofibrils
20
Q

The bedrest study by NASA and ESA 2019 investigated the influence of bed rest on skeletal muscle for up to 55 days. Three measurements over time were performed, where blood was drawn and a muscle biopsy was performed.
What happened to the myofibrillar Z-disc width after short- and long-term bed rest?

A

The width decreases after short- and long-term bed rest

21
Q

The bedrest study by NASA and ESA 2019 investigated the influence of bed rest on skeletal muscle for up to 55 days. Three measurements over time were performed, where blood was drawn and a muscle biopsy was performed.
What happened to the myofibrillar structure after short- and long-term bed rest?

A

Long-term bed rest disrupts myofibrillar structure, but not for short-term bed rest.

22
Q

What is the result of the decrease in Z disc width and disruption of myofibrillar structure?

A
  • Decrease in Z-width -> muscle atrophy
  • Myofibrillar structure disruption -> decrease in specific tension

Altogether, this results in a decrease in force generating capacity.

23
Q

The bedrest study by NASA and ESA 2019 investigated the influence of bed rest on skeletal muscle for up to 55 days. Three measurements over time were performed, where blood was drawn and a muscle biopsy was performed.

HOMA2-IR score is a method to assess insulin resistance.

What happened to the HOMA2-IR score after short- and long-term bed rest?

A

The score increases after short- and long-term bed rest.

24
Q

The bedrest study by NASA and ESA 2019 investigated the influence of bed rest on skeletal muscle for up to 55 days. Three measurements over time were performed, where blood was drawn and a muscle biopsy was performed.

HOMA2-IR score is a method to assess insulin resistance.

What else was found in the same study that could explain the increase in HOMA2-IR score after short- and long-term bed rest?

A

GLUT-4 translocation decreases after short- and long-term bedrest. Thus, less glucose can be taken up, resulting in higher lood glucose levels and a higher HOMA2-IR score.

25
Q

The bedrest study by NASA and ESA 2019 investigated the influence of bed rest on skeletal muscle for up to 55 days. Three measurements over time were performed, where blood was drawn and a muscle biopsy was performed.

What was found in regard to glycogen levels?

A

That glycogen does accumulate as a result of bed rest, but does not further accumulate from short-term bed rest (day 6) to long-term bed rest (55 days).

26
Q

The bedrest study by NASA and ESA 2019 investigated the influence of bed rest on skeletal muscle for up to 55 days. Three measurements over time were performed, where blood was drawn and a muscle biopsy was performed.

What was found in regard to lipid droplets?

A

That lipid droplets increased after both short- and long-term bed rest.

27
Q

The bedrest study by NASA and ESA 2019 investigated the influence of bed rest on skeletal muscle for up to 55 days. Three measurements over time were performed, where blood was drawn and a muscle biopsy was performed.

What else was found regarding lipid droplets?

A

That there were changes in lipid species (i.e. more ceramides, sphingomyelin, triglycerides, cardiolipins) as a result of insulin resistance induced by bed rest.

28
Q

The bedrest study by NASA and ESA 2019 investigated the influence of bed rest on skeletal muscle for up to 55 days. Three measurements over time were performed, where blood was drawn and a muscle biopsy was performed.

They also measured products of metabolism at baseline, short-term bed rest and at long-term bed rest. What conclusion was made based on the (change in) levels of these metabolism products?

A

That there is muscle metabolic inflexibility after bed rest.

29
Q

The bedrest study by NASA and ESA 2019 investigated the influence of bed rest on skeletal muscle for up to 55 days. Three measurements over time were performed, where blood was drawn and a muscle biopsy was performed.

What was found in regard to mitochondrial function?

A

That mitochondrial function was impaired after 55 days of bed rest, shown by decreased mitochondrial respiration, density, and area.

30
Q

The bedrest study by NASA and ESA 2019 investigated the influence of bed rest on skeletal muscle for up to 55 days. Three measurements over time were performed, where blood was drawn and a muscle biopsy was performed.

Summarize the most important findings.

A
  • Reduced ATP utilization rate
  • Reduced fatty acid oxidation
  • Lipid accumulation
  • De novo lipogenesis
  • Glycogen accumulation and insulin insensitivity
  • Metabolic inflexibility
  • Increased glucose oxidation
  • Lipotoxicity
  • Mitochondrial dysfunction
31
Q

How to combat sarcopenia and immunosenescence and therefore preventing hospitalization?

A

Healthy lifestyle:
* Resistance and balance training, prevention of inacitivity
* The right nutrition, prevention of catabolic state

32
Q

What is the most effective intervention to induce muscle hypertrophy?

A

Resistance exercise (in combination with protein intake)

33
Q

Besides an increase in muscle mass as a result of exercise. What else can be seen in the muscle as a result of exercise?

A

Increase in satellite cells (muscle stem cells)

34
Q

What is anabolic resistance? And what is the result of anabolic resistance?

A
  • Anabolic resistance describes the reduced stimulation of muscle protein synthesis to a given dose of protein/amino acids and contributes to declines in skeletal muscle mass.
  • Therefore, anabolic resistance increases protein requirement. But if increase in protein requirement is not met, this results in ICU admission, increased aging, chronic disease, and impaired recovery after hospitalization.
35
Q

Answer the following questions in regard to the effect of exercise to understand how exercise mitigates inflammaging:

  • What happens in adipocytes when exercising regularly?
  • What happen to the skeletal muscle when exercising regularly?
  • Which myokines produced by skeletal muscle have an effect on the immune system?
  • The change in skeletal muscle (e.g. which myo/cytokines are produced) also has an effect on the immune system: what happens to the thymus as a result of exercise?
  • The change in skeletal muscle (e.g. which myo/cytokines are produced) also has an effect on the immune system: what happens to naive T cells as a result of exercise?
  • The change in skeletal muscle (e.g. which myo/cytokines are produced) also has an effect on the immune system: what happens to NK cells as a result of exercise?
  • The change in skeletal muscle (e.g. which myo/cytokines are produced) also has an effect on the immune system: what happens to monocytes/macrophages as a result of exercise?
A
  • Adipocytes: reduction of visceral fat mass, increase in browning of adipose tissue, decreased macrophage infiltration, and macrophage polarization from M1 to M2.
  • Skeletal muscle: increased production of IL-6, IL-7, IL-15, IGF1, MTRNL, decrease in myostatins.
  • IL-6, IL-7 and IL-15 have an effect on the immune system.
  • Thymus increases RTE output (recent thymic emigrants -> naive T cells).
  • Naive T cells increase in survival and proliferation
  • NK cells increase in cell numbers, cytokine production and cytotoxicity.
  • Monocytes/macrophages increase in IL-10 and IL-1RA and decrease in TNF.

Exercise and Clinical Immunology (16 decks)

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