Impact of Ageing on Adipose, Muscle and Systemic Inflammation

August 22, 2018 updated by: William Trim, University of Bath
The accumulation and dysfunction of excess adipose (fat) tissue that occurs with ageing is associated with a number of chronic inflammatory disorders such as type 2 diabetes and cardiovascular disease but the underlying mechanisms are not understood.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Adipose tissue is a highly dynamic organ that produces a wide array of adipokines which can affect the function of other tissues throughout the body. The physiology of adipose tissue is a relatively new and exciting area of research and researchers are learning more about its complexity, in particular the way in which adipose tissue plays a dynamic and active role in various normal and pathological processes. Comparatively little is known about the changes that occur within adipose tissue over the natural course of ageing - and adipose dysfunction could play a role in ageing-related chronic systemic inflammatory diseases such as type 2 diabetes and cardiovascular disease.

In this study, the investigators would like to investigate inflammatory and metabolic changes that occur within adipose tissue with ageing. the investigators would also like to examine whether age-related changes in adipose tissue are specific to this particular tissue type by comparing adipose-resident immune cell populations and measures of inflammation and metabolism to those in muscle tissue and blood.

By exploring the immune dysfunction that occurs with ageing in adipose tissue and relating them to inflammatory and metabolic differences in muscle and blood, this work may potentially reveal causal mechanisms in the development of ageing-related chronic inflammatory diseases and ultimately lead to the development of better treatment/management strategies.

BACKGROUND Adipose tissue is sizeable endocrine organ and is highly dynamic, producing a wide array of adipokines which can affect a range of physiological processes including regulation of appetite, energy expenditure, insulin sensitivity, inflammation, endocrine and reproductive systems and bone metabolism. Ageing is a process that is associated with adipose tissue accumulation, changes in adipose tissue distribution and its dysfunction which in turn are linked to the development of chronic inflammatory disorders such as type 2 diabetes and cardiovascular disease.

Adipose tissue inflammation may be key Adipose tissue consists not only of adipocytes, but also many other cell types including endothelial cells, preadipocytes, immune cells such as macrophages and lymphocytes such that adipocytes themselves may only represent 60-70 % cell numbers in adipose tissue. Research from over the last decade or so suggests that the presence of immune cells within the adipose tissue itself are important in regulating both local and systemic inflammation/production of adipokines. For example, adipose tissue macrophages contribute the majority of the pro-inflammatory cytokine TNFα and ~50% IL6 secreted by adipose tissue, which show increased secretion with adipose tissue dysfunction and are implicated in the development of chronic inflammatory disorders. Changes in adipose resident immune cells have been relatively well studied in obesity but there are comparatively few studies in humans examining changes in immune cell populations and their potential impact on adipose tissue inflammation in the context of ageing. Given the time-course of adipose tissue accumulation in obesity compared to ageing, there is the potential for differences in the underlying mechanisms of adipose tissue dysfunction to occur.

In humans, there is overwhelming evidence (including work by the investigator's group) that macrophages accumulate in subcutaneous adipose tissue with obesity and are important mediators of adipose tissue inflammation. Additionally, work performed by this group has also shown that T cells in adipose tissue are more activated with obesity and this may also be related to levels of adipose tissue inflammation. Only one study has attempted to investigate the impact of ageing on immune cells in adipose tissue, however, this was in a very specific population (Pima Indians) and only up-to the age of 45 years so it is not known how immune cells change with further increases in age where chronic inflammatory disorders become more prevalent. Studies using mouse models indeed suggest that there are discrepancies in immune cell populations within adipose tissue following diet-induced obesity compared to ageing. In mice, it is not clear if there is a change in the number or just a change from an anti- to pro-inflammatory phenotype which would be in contrast to obesity, where there is evidence of both an increase in number and skewing towards a pro-inflammatory phenotype. Mice also show an increase in T-cells in adipose tissue with ageing - especially in T-regulatory cells, however, in diet-induced obesity there may be an increase in the number of pro-inflammatory effector cells (e.g. CD8+).

The potential role of adipose tissue inflammation in the development of age-related chronic inflammatory disorders and how this compares to the investigators' previous work in the context of obesity is something the investigators are keen to address in the present study.

Investigating tissue specific changes with ageing With ageing there is an increased deposition of adipose tissue within muscle and this can have profound effects on muscle tissue including inducing insulin resistance and lipotoxicity. Considering that muscle is one of the major sites for glucose uptake, impairment in this process can have a profound effect on systemic glucose concentrations and whole body insulin resistance. Like adipose tissue, muscle itself is host to resident immune cells, but it is not known whether these differ in terms of proportion or function to those found in adipose tissue. Furthermore, it is not known how these immune cells in muscle tissue may affect local and systemic inflammation in the development of ageing-related chronic inflammatory diseases. It is important to consider the role of different tissues in disorders that affect the body as a whole as there may be specific responses to ageing that need to be considered when trying to understand the underlying pathophysiology of ageing-related chronic diseases. Thus, the impact of ageing on muscle immune cells and inflammation is another factor that the investigators are keen to address in the present study. the investigators are especially interested in examining whether ageing affects adipose and muscle in a similar or different way.

Purpose The purpose of this study is to investigate inflammatory and metabolic changes in adipose tissue that occur with ageing and to compare these changes to those in muscle and blood.

By comparing metabolic and inflammatory parameters within adipose tissue, muscle and the circulation in younger and older individuals, the investigators hope to gain vital clues regarding the potential pathogenic mechanisms involved in the development of ageing-related chronic inflammatory diseases. With greater understanding of these mechanisms the investigators hope to prepare the ground for new and more effective means of prevention/treatments for ageing-related chronic inflammatory diseases.

Study Type

Observational

Enrollment (Anticipated)

24

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • Somerset
      • Bath, Somerset, United Kingdom, BA2 7AY
        • University of Bath - Department for Health

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 83 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Sampling Method

Non-Probability Sample

Study Population

general free-living public in the Bath and the surrounding areas

Description

Inclusion Criteria:

  • Male
  • Aged between 20-35 years (Group 1) or 65-85 years (Group 2)
  • Fat mass index based on DEXA between 4-8 kg/m2
  • Weight stable for more than 3 months (no change in weight +/- 3%)
  • Physical Activity Level (PAL) between 1.4 and 1.9
  • Non-smoker
  • Healthy

Exclusion Criteria:

  • Any chronic illness, cardiac, pulmonary, liver, or kidney abnormalities, uncontrolled hypertension, peripheral arterial disease, insulin- or non-insulin dependent diabetes or other metabolic disorders
  • Individuals who consume on a daily basis any analgesic or anti-inflammatory drug(s) including NSAIDs and corticosteroids, prescription or non-prescription
  • Taking any medications that may influence lipid or carbohydrate metabolism or immune system function
  • Individuals with a known negative reaction to lidocaine anaesthetic
  • Participation in heavy resistance training

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Other
  • Time Perspectives: Cross-Sectional

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Young males aged 20-35 years old

Maintaining a normal daily living lifestyle

  • Healthy
  • Reasonably active- PAL: 1.4-1.9
  • Non-obese- Fat mass index based on DEXA of 4-8kg/m2
  • Weight stable for more than 3 months (±3% body mass)
  • Non-smoker
  • No chronic illness, cardiac, pulmonary, liver, or kidney abnormalities, uncontrolled hypertension, peripheral arterial disease, insulin- or non-insulin dependent diabetes or other metabolic disorders
  • No daily consumption of analgesic or anti-inflammatory drug(s) including NSAIDs and corticosteroids, prescription or non-prescription
  • No medications that may influence lipid or carbohydrate metabolism or immune system function
  • No known negative reaction to lidocaine
  • No participation in heavy resistance training
Other: Maintaining a normal daily living lifestyle
participants will undertake a normal lifestyle with no alterations to daily living in order to access the differences in tissue (muscle and adipose) and systemic inflammation between the two age cohorts
Old males aged 65-85 years old

Maintaining a normal daily living lifestyle

  • Healthy
  • Reasonably active- PAL: 1.4-1.9
  • Non-obese- Fat mass index based on DEXA of 4-8kg/m2
  • Weight stable for more than 3 months (±3% body mass)
  • Non-smoker
  • No chronic illness, cardiac, pulmonary, liver, or kidney abnormalities, uncontrolled hypertension, peripheral arterial disease, insulin- or non-insulin dependent diabetes or other metabolic disorders
  • No daily consumption of analgesic or anti-inflammatory drug(s) including NSAIDs and corticosteroids, prescription or non-prescription
  • No medications that may influence lipid or carbohydrate metabolism or immune system function
  • No known negative reaction to lidocaine
  • No participation in heavy resistance training
Other: Maintaining a normal daily living lifestyle
participants will undertake a normal lifestyle with no alterations to daily living in order to access the differences in tissue (muscle and adipose) and systemic inflammation between the two age cohorts

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Differences in immune cell populations (macrophages/Tcells) in adipose tissue of young versus old males
Time Frame: through to study completion, an average of 14 months
through to study completion, an average of 14 months

Secondary Outcome Measures

Outcome Measure
Time Frame
the impact of ageing on mRNA expression of key metabolic and inflammatory genes in adipose tissue.
Time Frame: through to study completion, an average of 14 months
through to study completion, an average of 14 months
the impact of ageing on metabolic and inflammatory protein secretions (into culture media) from adipose tissue
Time Frame: through to study completion, an average of 14 months
through to study completion, an average of 14 months
differences in immune cell populations in muscle tissue and blood compared to adipose tissue from the same individuals and the impact of ageing on immune cell populations in muscle tissue.
Time Frame: through to study completion, an average of 14 months
through to study completion, an average of 14 months
the impact of ageing on mRNA expression of other key metabolic and inflammatory genes in muscle tissue.
Time Frame: through to study completion, an average of 14 months
through to study completion, an average of 14 months
activation/inhibition of e.g. insulin stimulated pathways in adipose and muscle tissues (for example assessment of Akt/IRS1 phosphorylation by western blot analysis).
Time Frame: through to study completion, an average of 14 months
through to study completion, an average of 14 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Bath

Investigators

  • Principal Investigator: Dylan Thompson, Professor, University of Bath

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2016

Primary Completion (Actual)

March 1, 2018

Study Completion (Anticipated)

October 1, 2018

Study Registration Dates

First Submitted

May 6, 2016

First Submitted That Met QC Criteria

May 16, 2016

First Posted (Estimate)

May 19, 2016

Study Record Updates

Last Update Posted (Actual)

August 24, 2018

Last Update Submitted That Met QC Criteria

August 22, 2018

Last Verified

August 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 16/sw/0003

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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