Table of Contents:
I'm hoping to start some discussion here with medicine on an area of research that will potentially change the fundamental way in which most physicians and other health professionals approach medicine in the near future.
The following is an excerpt from the article published recently in Nature Medicine:
Linda Partridge
Professor, Max Planck Institute for Biology of Ageing.
Human life expectancy has increased over the past 170 years in many parts of the world. Unfortunately, the healthy lifespan has not, and the period of life when a person lives with disability and illness at the end of life is growing, especially in women.
But ageing is malleable, and mounting evidence suggests that late-life ill health can be combated. In laboratory animals, including mice and rhesus monkeys, genetic, lifestyle and pharmacological interventions can increase not only the lifespan, but also the healthspan. In humans, improvements in diet and the implementation of physical exercise regimes can effect major health improvements, but better lifestyle is not enough to prevent age-related diseases.
The big hope is that 25 years from now, medical sciences will have progressed enough to enable people to have healthier and more active lives almost up until their eventual death. Going forward, the direct targeting of mechanisms of ageing, including with existing drugs, presents an opportunity to reduce disability and illness in late life. Sirolimus, an mTORC1 inhibitor, extends the lifespan of laboratory animals and in clinical trials has proved to boost the immune response of older people to vaccination against influenza. Other drugs, such as the combination of desatinib and the BCL-2 inhibitor quercetin, which kill senescent cells, are farther from the clinic but show promise. Plasma from younger mice has been shown to have a beneficial effect on the stem cell function of several tissues in older mice; work to identify the natural metabolites responsible for this effect could open up avenues for translation to the clinic. Geroprotective drugs, which target the underlying molecular mechanisms of ageing, are coming over the scientific and clinical horizons, and may help to prevent the most intractable age-related disease, dementia.
I will now expand on this and more thoroughly explain its significance – I've had productive conversations with a few physician academics in the past so I hope you may find this useful:
Geroscience
Progress in the basic science of ageing biology in the past few decades has now allowed biogerontology to advance therapeutic candidates for translation to the clinic. This has led to the birth of a nascent field distinct from geriatrics, gerontology and biogerontology – but one that seeks to bridge these with interventions in humans – called geroscience.
Geroscience is an interdisciplinary field that seeks to reconcile ageing biology with age-related disease. Its central hypothesis posits that – with ageing as the primary risk factor for chronic non-communicable diseases, perhaps our disease-specific approach in medicine where we treat chronic disease AFTER it has manifested is misguided and that treating the biological proccesses underlying ageing will result in vastly better healthcare outcomes.
Current approaches in medicine predominantly treats one disease at a time, but geroscience seeks to target ageing as the central risk factor and treat ALL age-related diseases at the same time. This diagram illustrates this conceptually – treating individual diseases merely extends life without appreciably affecting quality of life as the patient succumbs to the next disease in line, whereas treating ageing would shift the entire red line to the right.
Our disease-specific approach stems from the 'infectious disease' approach where diagnosis is based on patients presenting with clinical symptoms/signs, which are then treated – often described by proponents of preventive medicine as 'sick care' rather than healthcare. We know that the prognosis of age-related disease means that no one escapes from the long journey of decrepitude, even if we contract different age-related diseases at different chronological ages.
The Risk Factor of Ageing
Physicians have done well with hypertension/cholesterol/cardiac drugs etc in recent decades to extend lifespan, but by extending life with these drugs some evidence suggests that we have merely
increased the percentage of our lives spent suffering by opening ourselves up to other age-related diseases, such as alzheimers, cancer, sarcopenia, COPD, CKD, the list goes on… Geroscience seeks to treat ageing in a 'preventive' manner, so that we can spend a larger proportion of our lives in good health (increasing healthspan) rather than merely increasing lifespan and suffering from age-related diseases from these years of longer life.
Another problem we have here is that even if we could 'cure' individual diseases like CVD, or even the entire entity of cancer, each would only contribute about 2 years to life expectancy, and delaying ageing would yield far greater returns for healthcare spending ('Substantial Health and Economic Returns From Delayed Aging May Warrant a New Focus for Medical Research')
Delayed aging could increase life expectancy by an additional 2.2 years, most of which would be spent in good health. The economic value of delayed aging is estimated to be $7.1 trillion over fifty years. In contrast, addressing heart disease and cancer separately would yield diminishing improvements in health and longevity by 2060—mainly due to competing risks.
To understand how this astronomical estimation could possibly be justified, we need to consider how ageing interacts on a multisystem level with chronic diseases and functional decline. The approximate risk increase for smoking on lung cancer is 5x, but the risk increase from ageing is 1000x. Similarly, obesity as a putative risk factor for diabetes increases risk by 8x, but ageing is again an approximate risk increase of 1000x as explained by the endocrinologist/geroscientist Nir Barzilai (Metformin may hold anti-aging promise to increase ‘health span’). Various therapies, such as caloric restriction in animal models have shown 20-50% increases in lifespan; recapitulating even a 5% delay in ageing would generate far more QALYs than if we cured individual chronic diseases.
Visualising ageing as a risk factor:
https://mobile.twitter.com/mkaeberlein/status/1182921879855738880
https://imgur.com/gallery/i2mYKze
https://imgur.com/gallery/xZQi2dr
Reconciling ageing as not only the primary risk factor for a plethora of different chronic diseases, but also the aetiological reason, has been well-supported by evidence in recent decades of biogerontology research.
In phylogenetically diverse animal models, significant success has been seen in slowing or even reversing the pathological changes of ageing, with the more well-characterised interventions including manipulation of longevity genes, caloric restriction, exercise, rapamycin, and metformin.
Mayo Clinic Senolytics –
https://imgur.com/gallery/P66ZoJX
Research by the Mayo Clinic on clearance of senescent cells suggests that ageing phenotypes are preventable, and that treatments are effective even in late life.
nature.com/articles/s41591-018-0092-9
Key Journal Articles
Identification of 12 genetic loci associated with human healthspan
https://www.nature.com/articles/s42003-019-0290-0/figures/1 Note carefully the y-axis Log scale, this demonstrates that ageing is associated with an exponential increase in risk of chronic diseases.
'The Hallmarks of Aging'
This paper is on track to become one of the most cited papers in biology with nearly 5000 citations in only 6 years since publication in Cell. It was indubitably inspired by the Hallmarks of Cancer papers also published in Cell that many here would be familiar with.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/
'Geroscience: Linking Aging to Chronic Disease'
The rationale for geroscience, published in Cell.
https://www.sciencedirect.com/science/article/pii/S009286741401366X
'Interventions to Slow Aging in Humans: Are We Ready?'
https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12338
'From discoveries in ageing research to therapeutics for healthy ageing
Review article published this year in Nature.
https://www.nature.com/articles/s41586-019-1365-2
'Metformin as a Tool to Target Aging' (TAME trial)
In the TAME study, we plan to enroll 3,000 subjects, ages 65–79, in ~14 centers across the U.S. Rather than study the effects of metformin on each separate condition, we will measure time to a new occurrence of a composite outcome that includes cardiovascular events, cancer, dementia, and mortality. TAME will also assess important functional and geriatric end points.
This is a 5 year multimorbidity RCT looking at ageing as a 'disease' which had been approved by the FDA years ago but only recently its $75 million funding. We know that multimorbidity has become increasingly "recognized as the most common chronic medical condition" and is the norm in elderly patients. Future clinical trials targeting ageing will assess multimorbidity outcomes, and the rationale behind the TAME trial is to serve as proof-of-concept. This is based on research finding that metformin extends healthspan and lifepsan in mice, and epidemiological data showing reduced cancer risk, reduced Alzheimer's risk, and even reduced mortality in treated diabetics compared to untreated non-diabetic controls (implying that metformin's effects actually outweighs the harm of diabetes), consistent with the idea that metformin may act on longevity pathways independent of its antidiabetic MoA. While biogerontologists don't expect metformin to exhibit large effect sizes in terms of the TAME trial's primary endpoints, due to modest effects in comparison to other therapeutic candidates from the lab, the trial will serve to establish the idea that ageing should be an indication for Pharma companies to pursue.
Metformin improves healthspan and lifespan in mice
https://www.nature.com/articles/ncomms3192
Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis
https://www.ncbi.nlm.nih.gov/pubmed/28802803
While the FDA has indeed approved the TAME trial to go underway, ageing is not recognised as a 'disease'. Now we can debate about the semantics of what defines a 'disease', but pragmatically speaking it isn't particularly relevant to the candidate therapies of biogerontology. There are certainly increasing signs of change in how we are thinking about ageing – in 2018 the WHO added the code
'ageing-related' XT9T to the ICD-11. While ageing is not recognised as a disease, it is clear that the TAME trial's purpose is to treat 'ageing' according to its primary endpoints – in all but name.
However, this could be fairly problematic as the current 'anti-ageing' industry of vitamins, supplements, cosmetics and alternative medicines – an industry rife with unproven snake oil – has no FDA regulation. It was a $281.6 billion industry in 2015, yet, if ageing is recognised as a disease then these will be scrutinised for FDA review.
While there is a major distinction between geroscience and the current 'anti-ageing' industry, it is clear that ageing is not yet recognised as an indication that is relevant to the FDA, and pharmaceutical + insurance companies.
Indeed, there are currently dozens of clinical trials with novel therapeutics that target ageing, but the problem of a lack of indication for ageing is bypassed by continuing to operate under the single-disease model. Unity Biotechnology is one such company currently conducting phase II clinical trials for senolytics against osteoarthritis. They had an IPO of $300 million in 2018 which is unheard of in biotech as at the time as they did not even have phase I data – this kind of valuation is typical of companies with phase II/III data.
The private industry has well and truly taken off, with an exponential increase in number of biotech startups and funding over the last decade, along with the longevity industry being valued at $27 trillion by 2026. Even Google, a tech company, has founded a company called Calico with the explicit goal of extending lifespan – they partnered with Pharma company AbbVie with a partnership for $2.5 billion in the last 5 years.
I hope this writeup has provided a brief overview of geroscience and the longevity industry, and shown its increasing relevance to the future of clinical medicine. It is therefore imperative that current and future physicians have some awareness of the geroscience approach to medicine as such research transitions to the clinic.
Source: Original link
