Comment: Find drugs that delay many diseases of old age

Professor Ilaria Bellantuono from the University of Sheffield's Department of Oncology and Metabolism explains why we need treatments that boost resilience to multiple age-related diseases and why simply extending lifespan is not enough.

Find drugs that delay many diseases of old age

By Professor Ilaria Bellantuono 14.02.18 originally posted in Nature

By 2050, the number of people over 60 years old is expected to reach two billion worldwide, or 22 per cent of the population. In 2015, it was 12 per cent of the population. And for many, a longer life will mean more years of chronic diseases, such as arthritis, type 2 diabetes, cancer and Alzheimer’s disease. In Europe, for example, the estimated life expectancy for women born in 2014 is 1.6 years longer than for those born in 2006; for men, it is 2.3 years longer.

But the women born in 2014 can expect 0.7 fewer years of good health, and the men zero (see ‘More years of what?’). As this trend continues, health-care and other costs are expected to soar.

A class of drugs called geroprotectors might be able to delay the onset of concurrent age-related diseases (multimorbidity) and boost resilience. In various animal models, these drugs can ward off problems of the heart, muscles, immune system and more.

And in 2014, investigators reported the results of the first clinical trial of a geroprotector in people over 65: the drug, RAD001, boosted immune responses to an influenza vaccine.

More than 200 compounds have now been classified as geroprotectors. But various factors are preventing these drugs from reaching the clinic. Here we set out three steps required to speed up translation. These have been distilled over the past three years by a network of academic and industry scientists, clinicians and regulators called COST Action BM1402: MouseAGE. The network, which is funded by the European Union, has worked with other experts in these domains worldwide.

Maturing field

Over the past decade, understanding of the physiological changes that occur as people age has improved a great deal. Common mechanisms seem to underpin several age-related diseases, including diabetes, Parkinson’s disease and Alzheimer’s.

A review of more than 400 studies of people and animal models indicates that similar mechanisms underlie six conditions. These can involve DNA damage, such as that caused by free radicals; cellular senescence (in which cells stop dividing and start secreting inflammatory factors); or inflammation and autophagy (the degradation of organelles, misfolded proteins and so on).

This may explain why people over 65 are at a higher risk than younger people of developing more than one disease at the same time. In the United States, 7 out of 10 people over 65 with diabetes will die of heart disease, for instance. It is also becoming clear that one agerelated disease can accelerate the onset of others.

A 2014 study showed that people older than 75 who already had diabetes, say, were more than twice as likely to develop another disease over the next three years than those who were healthy at the beginning of the study. Also, between one-quarter and half of people over the age of 80 become frail. The accumulation of deficits makes it harder for them to recover from an infection, fall or other minor stressor.

It is unclear whether multimorbidity leads to frailty or vice versa, or whether they are independent. Until now, ageing research has focused mainly on single diseases, or on delaying death. This means that the fundamental mechanisms of ageing as targets for the treatment or prevention of several age-related conditions are being missed. What’s more, patients with multimorbidity are being exposed to many drugs at once, often with adverse effects.

Three steps to translation

Research in mice over the past few years suggests that it might be possible to delay the decline of many tissues and the onset of disease. Drugs such as rapamycin, metformin or senolytics (which remove senescent cells), can slow the development of cataracts, osteoarthritis, osteoporosis, the loss of muscle mass and can improve cardiac function. If these are to become useful in people, three advances must be made.

More years of what?

In Europe, men and women are living longer. They are also spending more years with chronic conditions such as diabetes, cancer and Alzheimer's disease.

For drugs to be approved for clinical use, developers must first identify the indication — the condition that enables investigators to obtain authorization to test a drug treatment in people.

Professional organizations, such as the International Association of Gerontology and Geriatrics, must agree on definitions of multimorbidity and frailty. And institutions such as the World Health Organization (WHO) and the US Centers for Medicare and Medicaid Services (CMS) need to accept this consensus.

(The CMS issues codes that affect people’s ability to claim health insurance for the treatment of a particular condition.) There is no standardized definition of multimorbidity. Some researchers use the term to describe the co-occurrence of two diseases, some five, others 13 and so on. This makes it hard to compare studies and to establish which diseases have a higher chance of occurring together. Agreeing to a definition will require: working out which of the five or 10 most burdensome age-related diseases, say, to prioritize; which of these are most likely to associate together; the timing of development of each disease with respect to the others in the cluster; and the identification of the pathways associated with their common pathogenesis.

Likewise, there is no consensus on the definition of frailty, although clinicians and researchers are generally in agreement about its usefulness as a clinical term. Nor are there standardized assessments of frailty. Some describe a person as frail if they show three or more of the following: weakness, slowness, low levels of physical activity, self-reported exhaustion and unintentional weight loss.

A more quantitative approach attempts to capture the accumulation of deficits (including hearing loss, low mood and dementia) in a ‘frailty index’.

Over the past three years or so, at least six major international societies have held meetings to try to encourage scientists and clinicians to reach a consensus on the definition of frailty.

These have involved the International Association of Gerontology and Geriatrics and the International Academy of Nutrition and Aging, among others. Such efforts should be scaled up and accelerated with the leadership of a coordinating body such as the WHO, the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Improve animal models. There are many mouse models for type 2 diabetes, Alzheimer’s disease, stroke, cardiovascular diseases, osteoarthritis and osteoporosis12. However, to save costs and time, the desired pathology is generally induced when lab mice are two to six months old. (The average lifespan for the most commonly used lab mouse is 22 months.)

Researchers might delete a key gene, for instance, or remove a particular organ (such as the ovaries) to induce a disease (such as osteoporosis). This means that the effects of cellular ageing on disease progression are rarely taken into account. We urge investigators to develop mouse models in which diseases are induced in aged animals.

Some researchers have proposed models of multimorbidity that use certain strains in which the ageing process is accelerated. Mice that have had the DNA-damage-repair gene Ercc1 deleted, for example, develop dysfunction in multiple tissues. Again, we recommend that such phenotypes are induced in older mice.

So far, the few attempts that have been made to develop mice models for age-related multimorbidity have met many challenges; in some cases, genetic alterations expected to worsen conditions have improved them. It could be that researchers need to delete multiple genes, with one gene — or several.