Shift Bioscience is a biotech startup targeting the root causes of aging to extend healthy lifespan.
THE AGING CHALLENGE
Between the ages of 20 and 70 our risk of death from disease increases exponentially. This leads to a matching exponential increase in healthcare costs. The 65+ age group incurs four to five times the health care costs of the under 65s. Globally, over-65s number 600m people today and this will increase to 1.2 billion by 2050. This inevitable rapid aging of the population will create an unsustainable burden on healthcare budgets. In the US this represents an additional $800 billion annual ‘tax’ that will need to be paid, either by insurers, taxpayer or patients themselves.
Today’s available therapies for age-related diseases deal with the symptoms but not with the underlying causes of disease. There is an urgent imperative to develop new therapies based on our rapidly-expanding knowledge of what causes aging at the molecular level.
New epigenetic tools have given scientists the ability to examine the hallmarks of aging and to determine which of these are root causes and which are consequences that sit downstream of these root causes. These new insights can be used to guide the development of a new generation of more effective therapies for age-related diseases.
THE MOLECULAR BIOLOGY OF AGING
Aging arises from dysfunction in several cellular processes interacting together, commonly referred to as the ‘hallmarks of aging’. Biopharma companies are targeting different hallmarks of aging to develop new drugs to combat age-related diseases, but the question of which hallmark is more or less central to aging has remained a subject of debate.
The recent discovery and experimental use of a highly accurate aging biomarker (Horvath’s multi-tissue epigenetic aging clock) has revealed that some hallmarks have a significant impact on the aging clock whilst other hallmarks have little or no effect. It follows that targeting specific central hallmarks which have the greatest observed effect on the clock will have the greatest impact on slowing or reversing processes of aging.
We are working in two related areas. First, to develop next-generation epigenetic clocks suitable for genetic screening (e.g. CRISPR) or pharmaceutical screening, helping researchers to increase the power of their pre-clinical studies and reduce timescales. Second, using this platform and the insights which we have gained into the epigenetics of aging, to identify novel drug molecules which are more effective in decelerating the epigenetic aging clock.
Seeking drugs that target age-related diseases by measuring their effect on the epigenetic clock is a new way to approach the challenge of developing effective therapies. We have already identified one such family of small molecules that decelerate the clock by at least 50%. The mechanism of action involves the restoration of mitochondrial integrity and function which is progressively lost in older cells. This leads to a beneficial shift in the epigenetic programming of the cell.
THE CHALLENGE OF HEART FAILURE
During the past half-century, the advances in the prevention, diagnosis, and management of cardiovascular disease (CVD) have been nothing short of spectacular. Age-adjusted CVD-related deaths have declined by about two-thirds in industrialized nations. Heart failure (HF) is an age-related disease which represents a notable exception to these encouraging trends. Annual hospital admissions for patients with a primary diagnosis of HF now exceed 1 million admissions per year in the US, and HF patients make more than 3m physician visits per year.
The costs of HF in the United States were estimated at US $39.2 billion per annum by the American Heart Association in 2010. The estimated lifetime cost of HF per individual patient is $110,000/year with more than 75% of this cost consumed by in-hospital care. Five-year mortality is approximately 50%, which is worse than that of many cancers.
Heart failure can be classified into two primary types with approximately equal prevalence: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Whilst there are some recently-approved drugs that are effective in treating HFrEF, there are no effective disease modifying drugs yet approved for either type of heart failure.
MELAS – A RARE MITOCHONDRIAL DISEASE
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a rare mitochondrial disease caused by mutations in mtDNA inherited from the mother. Symptoms usually appear in childhood and become increasingly severe with age. The condition is systemic affecting many parts of the body, particularly the heart, brain and muscles.
We have selected MELAS as our first disease target because the root cause – mitochondrial dysfunction caused by mutations in mtDNA – is well understood with a high level of consensus among clinicians, and we have demonstrated strong proof-of-concept in pre-clinical studies. We have been able to reduce the level of MELAS mtDNA mutations and restore cellular energetic function in fibroblast cells taken from MELAS patients.
The authors used electron cryo-tomography (cryo-ET) to visualize mitochondrial nucleoids, from which this 3D reconstruction resulted.
Dr Christian Kukat, Dept of Mitochondrial Biology, Max Planck Institute for Ageing, Cologne; Prof Nils-Goran Larsson, Department of Laboratory Medicine, Karolinska Institutet, Stockholm
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