Targeting mechanisms of ageing with geroprotectors to maintain musculoskeletal health

Lead Research Organisation: University of Sheffield
Department Name: Oncology and Metabolism

Abstract

As we get older, the quality of our bones and joints deteriorates. These changes make it more likely that we will develop osteoporosis and osteoarthritis. In osteoporosis, patients lose significant amounts of bone tissue, leaving their bones less dense and at a much greater risk of fracturing. When an older patient suffers a bone fracture, recovery is difficult and they often lose mobility and independence. Patients with osteoarthritis suffer from pain and stiffness in their joints, which also reduces their mobility. Osteoporosis and osteoarthritis are often linked. A patient with osteoarthritis, for example, may also show signs of bone loss in the affected limb. Together those two diseases are a major cause of visits to GP surgeries and cost over £5 billion per year to the NHS. Each disease is often treated separately, with patients required to take many drugs. Not only is the administration of multiple drugs costly, but patients can also suffer more side effects. In addition, drugs sometimes work less well when they are given in combination with other medicines that are unrelated.
A new way of treating multiple diseases related to ageing, such as osteoporosis and osteoarthritis, is now emerging. It is based on the idea that ageing per se plays a major part in the development of these diseases and that drugs designed to delay the onset of ageing may also be able to delay the onset of age-related diseases. The reasoning is that cells in the body's tissues work less well as we age because the cells are ageing too - accumulating damage to their DNA and protein 'building blocks', for example. The tissues consequently deteriorate in quality and become more prone to disease.
Researchers now have good evidence that if we keep our cells in a youthful state by interfering with the factors that cause cells to age, the cells will work better. This has been shown in studies using mice. When drugs that are known to keep cells in their youthful state were given to mice, the mice lived longer than animals which were not given the drugs. Tissues such as the heart and muscle were also kept healthier and in better working order. At the moment, we don't know whether these drugs can keep bones and joints in a youthful and healthier state as well. This is what we plan to investigate in this study. We will collaborate with the US-based National Institute of Ageing Intervention Testing Programme, a group that is renowned for their success with this type of work. The US researchers are continuing to test these drugs on mice, so they can determine how much longer the mice live. We are collecting bones and joints from these same mice following their treatment with three different drugs (rapamycin, 17alphaestradiol and acarbose). We will assess whether the joints and bones of these mice are any healthier. Our laboratory has an excellent track record in the analysis of bone and joints and we have access to all the techniques required.
If this work shows that drugs which delay ageing can also promote the health of the skeletal system we will then seek more funding for a follow-on study. This would use animal models again, and examine specifically whether these drugs prevent the onset of osteoporosis and osteoarthritis and improve the function of the skeletal system. Such findings would also pave the way for new ways of thinking about how to identify new treatments for age-related diseases.

Technical Summary

Musculoskeletal diseases are one of the major causes of GP consultations and are worth 5 billion/year in NHS costs. Age is the major risk factor for the onset of musculoskeletal diseases such as osteoporosis (OP) and osteoarthritis (OA) and is associated with deterioration of bone and cartilage. This deterioration is thought to predispose to the development of OA and OP. Recent findings showed that drugs, which target fundamental mechanisms of ageing (geroprotectors) extend the lifespan of animal models and prevent the loss of function observed in tissues such as heart, muscle and immune system with age (healthspan). However, their effect on bone and joint health has not been investigated. In this proposal, we want to test whether geroprotectors improve bone and joint health with age. We will test 3 geroprotectors, rapamycin, 17alphaestradiol and acarbose, which have been selected based on their mechanism of action. They reduce oxidative stress, senescence and boost autophagy resulting in extension of lifespan in mice. Dysregulated oxidative stress, senescence and autophagy have been shown to play an important role in the onset of OA and OP. Therefore it is expected that these drugs will have an effect on both bone and joint health. To perform this project we have access to data on longevity and bone and joint tissue from mice treated with these drugs as part of the National Institute of Ageing Intervention Testing programme. We will use state of the art bone analysis well established in our laboratories, such as ex vivo X-ray microCT and histomorphometry combined with new computational approaches that we have developed for an in depth structural analysis of bone, bone strength, cartilage degradation and subchondral bone changes. The combination of these data will allow us to determine whether longevity and healthspan are closely associated and whether blocking oxidative stress, senescence and autophagy maintain health of the skeletal system with age.

Planned Impact

Over 60% of people over 65 years old have multimorbidity and over 50% shows sign of frailty. Over 80% of the medicare budget is spent on multimorbidity and frailty. Musculoskeletal disorders are among the most important contributors to this budget. In addition musculoskeletal disorders are responsible for a third of working days lost due to ill-health. Treatment of each disease individually is not working due to problems of polypharmacy with increased side effects and reduced efficacy. With the segment of the population over 60 years old fast growing costs are forecasted to become unmanageable in the near future. Drugs, which may improve health in multiple tissues and prevent the onset of multimorbidity and frailty are very attractive. However, more knowledge is required to strengthen the evidence and persuade industry, regulators and policy makers to invest in this area. In particular a major block to investment and translation is the fact that there is no appropriate regulatory framework to grant permission for testing this class of drugs in patients in Europe. This is because ageing is not a disease and longevity is not an accepted endpoint in clinical trials. Approval for drug testing in man are granted only for specific diseases, with measurable endpoints which benefits patients' life. For this reason it is of the utter importance that we understand whether these drugs improves health rather than longevity. This will pave the way to further funding to identify whether diseases can be prevented by maintaining health and which measurements can be used to test any early improvement in patients' which benefits their well-being. The knowledge developed will be of interest to
1. Pharma industry (Impact to be realised in the next 5-10 years). This will open new pathway for drug development. IB has numerous contacts with industrial partners, particularly Novartis, who are very interested in this area of research. She will continue to liaise with them and present data as soon as they become available. Novartis has tested a new rapalog to rejuvenate immune cells. The testing of rapamycin on joint and bone health will provide a new application for this molecule.
2. Policy makers and funders (impact to be realised in the next 5-10 years). Geroprotectors have been overlooked in the UK. This is in contrast to the USA where large amount of funding have been dedicated to their testing. The healthspan campaign has been launched to explain to the public and policy makers in the USA the potential of this class of molecules. In the UK this concept is only well established in a very small community of scientists involved in ageing research. There is an urgent need for strong supporting evidence of the potential of these drugs and a dissemination strategy to persuade policy makers to recommend strong investment in this area. This will also persuade regulators to prepare the appropriate regulatory framework for fast tracking of first in man studies in this area. This data will contribute to build the evidence for the development and use of geroprotectors to prevent age-related musculoskeletal diseases and beyond.
3. Regulators for approval of new medicinal products (impact to be realised in 5-10 years). The approval of drugs by the Medicine and Healthcare Product Regulatory Agency (MHRA) requires the identification of a disease, appropriate models of disease and validated measurements. Preventive treatment for musculoskeletal health is not a recognised conditions. IB is working with Henry Stemplewski, at MHRA through MouseAGE to determine the data package required for such molecules to be approved for first in man testing.
4. Older people. (impact to be realised in 15-20 years) OP and OA are chronic, highly invalidating diseases, with pain, loss of mobility and independence, affecting quality of life. Ways to contract the period of morbidity before death will improve the quality of life of older people.

Publications

10 25 50
 
Description We have analysed the effect of Acarbose, 17 alpha estradiol and Rapamycin (drugs which have been shown to extend lifespan) on bone structure, stiffness and strength and joint health with age.

We have found regional changes in bone volume/tissue volume (BV/TV) in both males and females at 12 months of age in mice treated with Acarbose and 17alpha estradiol but not at 22 months using our novel partition method. Whilst in males there were areas of loss and areas of gain, in females there was a significant increase in BV/TV in the antero-medial part of the bone. However, these increase were small and did not affect the strength and stiffness of the bone obtained using FE models. Mice treated with rapamycin had no significant differences using the partition analysis in males and females.We have also analysed the same bones using the more traditional morphometric analysis. No significant differences were found in the bones of mice treated with Acarbose at any age in males and females, suggesting that any change observed with the partition method were very small. In contrast a significant increase in cortical bone volume/tissue volume was observed in female mice at 12 months of age when treated with 17 alpha estradiol. This change was not observed in trabecular bone or in male mice in both trabecular and cortical bone. Histomorphometric analysis is ongoing to understand whether there are cellular changes underpinning the increase in bone volume/tissue volume. A significant increase in trabecular bone was observed in female mice treated with rapamycin at 22 months. This is very small and require further investigation to determine whether the size of the effect is biologically meaningful.

No significant changes were seen in joint health by OARSI score of the cartilage for Acarbose and 17alpha estradiol. In contrast a significnat improvement was observed in the joint of mice treated with rapamycin when assessed at 12 months but not at 22 months.

These data suggest that extension of lifespan is not a proxy for healthspan in the skeletal system. Some effects have been shown in bone and joint with some of the
life extending drugs but the effect is not consistent and is very modest.
Exploitation Route Once we will finish the analysis we will publish. Geroprotectors are a new class of drugs. in many study extension of lifespan has ben used as proxy for healthspan. here we show that this is not the case and therefore heathspan of each tissue should be tested for each drug. The skeletal system seem to be particularly resistant to benefit from these group of drugs.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description ECTS meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was a poster presentation. About 15 people came to the poster to discuss the work. there was discussion on how drugs which extends lifespan do not necessarily extends healthspan in the skeletal system
Year(s) Of Engagement Activity 2019
 
Description MRC- Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing Annual Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact This was an oral presentation which sparked discussion, particularly because we did not see an effect of geroprotectors as expected.
Year(s) Of Engagement Activity 2019
 
Description NC3Rs In Silico preclinical investigations of bone health 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact 30 researchers attended followed by a discussion
Year(s) Of Engagement Activity 2018
 
Description Oliviero 8th World Congress of Biomechanics, "Effect of age on the morphological and mechanical properties of the mouse tibia. poster 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was a poster presentation at the largest international conference in the field and sparked interesting discussion
Year(s) Of Engagement Activity 2018