- Email: [email protected]
Aging: therapeutics for a healthy future
Journal Pre-proof AGING: THERAPEUTICS FOR A HEALTHY FUTURE Robert Hodgson, Brian K. Kennedy, Eliezer Masliah, Kimberly Scearce-Levie, Barbara Tate, Anjli Venkateswaran, Steven P. Braithwaite
PII:
S0149-7634(19)30134-4
DOI:
https://doi.org/10.1016/j.neubiorev.2019.11.021
Reference:
NBR 3609
To appear in:
Neuroscience and Biobehavioral Reviews
Received Date:
13 February 2019
Revised Date:
22 September 2019
Accepted Date:
25 November 2019
Please cite this article as: Hodgson R, Kennedy BK, Masliah E, Scearce-Levie K, Tate B, Venkateswaran A, Braithwaite SP, AGING: THERAPEUTICS FOR A HEALTHY FUTURE, Neuroscience and Biobehavioral Reviews (2019), doi: https://doi.org/10.1016/j.neubiorev.2019.11.021
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
AGING: THERAPEUTICS FOR A HEALTHY FUTURE Running title: Aging Therapeutics Robert Hodgson1, 2, Brian K. Kennedy3, 4, Eliezer Masliah5, Kimberly Scearce-Levie6, Barbara Tate7, Anjli Venkateswaran2, Steven P. Braithwaite8 1Charles
River Laboratories, Wilmington, MA, Biology, Takeda San Diego, CA, 3Departments of Biochemistry and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 4Buck Institute for Research on Ageing, 5National Institute of Aging , 6Denali Therapeutics, 7Dementia Discovery Fund, 7, 8Alkahest Inc, San Carlos, CA
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Corresponding Author: Steven P. Braithwaite, Alkahest Inc. 125 Shoreway Road, Suite D, San
Approaching aging as a target is a new therapeutic frontier Potential of modifying aging processes can be transformative for medicine Multiple mechanisms have the potential to deliver improvements in healthspan Challenges of science, translation, economics and regulation need to be navigated Encouragement from collaboration between academia, industry, funders and regulators
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Highlights
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Carlos CA, 94070. Phone: +1-650-801-0470; Email: [email protected]
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Abstract
Increased healthcare and pharmaceutical understanding has led to the eradication of many childhood, infectious and preventable diseases; however, we are now experiencing the impact of aging disorders as the lifespan increases. These disorders have already become a major burden on society and threaten to become a defining challenge of our generation. Indications such as Alzheimer’s disease gain headlines and have focused the thinking of 1
many towards dementia and cognitive decline in aging. Indications related to neurological function and related behaviors are thus an extremely important starting point in the consideration of therapeutics. However, the reality is that pathological aging covers a spectrum of significant neurological and peripheral indications. Development of therapeutics to treat aging and age-related disorders is therefore a huge need, but represents a largely unexplored path.
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Fundamental scientific questions need to be considered as we embark towards a goal of improving health in old age, including how we 1) define aging as a therapeutic target, 2)
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model aging preclinically and 3) effectively translate from preclinical models to man. Furthermore, the challenges associated with identifying novel therapeutics in a financial, regulatory and clinical sense need to be contemplated carefully to ensure we address the
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unmet need in our increasingly elderly population. The complexity of the challenge requires different perspectives, cross-functional partnerships and diverse concepts. We seek to raise
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issues to guide the field, considering the current state of thinking to aid in identifying roadblocks and important challenges early. The need for therapeutics that address aging and
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age-related disorders is acute, but the promise of effective treatments provides huge opportunities that, as a community, we all seek to enable effectively as soon as possible.
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Keywords: Aging, neurodegeneration, review, longevity, healthspan
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Aging – What Are We Attempting to Treat? Many consider aging as a purely chronological phenomenon; it is an immutable fact that we all get older. However, this is a simplification as individuals all age functionally in different ways and the concept of “biological aging” is more relevant than chronological aging.1 When we consider biological aging, we have a therapeutic target, not simply targeting getting old, rather treating physiological decline that is manifested by dysfunction and morbidity in late
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life. When biological aging becomes pathological, it can be considered as a failure of homeostasis. There is a progressive component, but ultimately a point is reached at which
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there is inability to counter the amassed toll on the body of time-dependent accumulation of cellular damage (DNA mutations, protein misfolding, oxidative stress etc.), which occurs throughout life. With age, cellular processes (including stress response pathways invoked
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by damage) become less efficient, ultimately leading to cellular death and irreversible consequences. At younger ages, the body is able to mount compensatory responses and life
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is healthy. During middle age, the body’s ability to maintain homeostasis declines, resulting in chronic diseases that accelerate the gradual degradation of life quality, resulting in severe
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detriments, frailty and, eventually, mortality. There are many ways that a homeostatic balance can be maintained, giving many opportunities for development of therapeutics.
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When considering therapeutic outcomes, it is also important to consider the primary goal. Lifespan extension is an obvious target, but controversially there may be a maximum lifespan 2 and, more importantly, long life with low quality of life may be even less desirable. Instead, the concept of improving healthspan, the time of life in which we are healthy, is more realistic and one that many aspire to – being healthy in old age - whether or not this also
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leads to a longer life. The pathways modulating lifespan and healthspan are likely overlapping but distinct. Many interventions extend both in animal models, but different genes have also been associated with longevity versus disease-free aging in human studies.3 Age is a major risk factor for many chronic diseases, including those with huge impact on individuals and society such as Alzheimer’s disease (AD), cancer, cardiovascular disease, and diabetes.4 Aging is also a complex, multifactorial process. Key “pillars” or processes of aging 3
have been identified, including inflammation, macromolecular damage, and breakdown of proteostasis, epigenetic changes, and accumulation of senescent cells.5, 6 These pillars of aging link organ systems too, the brain clearly impacted by neuroinflammation, deficits in proteostasis leading to accumulation of aggregate-prone proteins and loss of stem cells in key areas involved in memory formation. Also in the periphery, from bone to skin to core organs, the biology of aging has widespread impact (Figure 1). These mechanistic processes are also highly intertwined, so that perturbation of one process can ramify throughout the whole
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system. This complexity and interdependence could lead to the inability to impact the system by intervening with the targeting of only one gene or with one single drug. However, it seems
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likely that a single event or small number of events can push “normal” aging over the edge into chronic disease. Thus, specific genetic mutations and single drugs can increase lifespan, including rapamycin and sirtuin-activating compounds7 across a range of animal models
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including C. elegans, D. melanogaster and M. musculus.8, 9
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There is still a lot that we don’t know about aging, with organisms within a species often showing considerable variability in both lifespan and healthspan. For example, some older
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people maintain good cognitive function throughout age, even as centenarians, whereas others develop dementia in middle age. This variability is due to stochastic as well as genetic and environmental factors; even isogenic individuals of a single species (C. elegans or M.
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musculus) raised in the same environment show wide differences in lifespans and ages of onset of degenerative pathologies.10-12 Understanding why these differences occur and how they contribute to pathological aging is an essential to guide the development of novel therapeutics. We also need to understand if there are mechanistic differences between normal and pathological biological aging, or if pathological aging is just accelerated biological
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aging. Likely, it is a combination, with these complex disorders of old age being an accumulation of multiple disease specific risk factors, environmental exposures and aging processes, where modifying even one component prior to overt disease may be able to alter the onset and/or course of multiple diseases.
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Attractively, if you can delay negative
aging processes, keeping people healthier as they age, an array of serious age-related disorders could be prevented. It is clear that increased understanding of the biology of aging can lead to wholly new therapeutic approaches of great potential impact. 4
Issues Involved in Developing Anti-Aging Therapies A therapeutic that halts or prevents aging, putting off the onset of a debilitating disorder, could lead to a longer life. Extending life on the face of it is highly positive; the vast majority of the population looks forward to a long and fruitful life. However, if anti-aging therapies only increase lifespan without increasing healthspan it will just increase the population of diseased elderly, increasing healthcare spending and providing an undesirable,
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unsustainable, future for society. If healthspan is increased, thus delaying the onset of an array of age-related disorders there could be a highly positive societal and economic impact.
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People could work longer, contribute more economically and have a more positive, productive life with a concomitant reduction in chronic health-related disorders. This would potentially lead to later retirement (an event likely to happen anyway with the aging of the
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population), and changes in population distribution, as longer lifespan correlates with reduced populations. The ethical implications must always be kept in mind, but the
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advantages and impacts of developing anti-aging drugs to improve the quality of life in old
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age are highly significant.15
Multiple Challenges of Developing Anti-Aging Therapeutics With the lofty goal to counteract aging, development of novel therapeutics will encounter a
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series of challenges, many of which have little or no precedent in prior clinical efforts. In particular, it is not clear how to design a clinical trial to assess strategies to slow the progression of aging per se. For diseases with a degenerative component, such as AD, trials often last many years, which is necessary to observe therapeutic effect over a slow rate of neurodegenerative decline. Independent of neurodegenerative disease, the rate of purely
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age-related decline may even be slower, and more variable between individuals, likely requiring even larger trials of longer duration. Moreover, therapies that require intervention earlier, in pre-symptomatic states, will require trials of extremely long duration, uncertain outcome and include immense heterogeneity. Designs will be based on outcomes of animal studies, where the aging time course differs dramatically from human aging and is likely different in many ways.
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Mouse models will be critical to identify new links between aging and disease, but it is important to note that while inbred mouse strains are likely to have relatively more homogeneous cohorts, outbred mice that are more representative of aging in human populations show more variation in aging processes. 16 Thus, how rodent outcomes translate to human trials remains unclear and the question of when it is best to start an intervention will be to an extent empirical from multiple human studies. New approaches to animal model development can allow researchers to evaluate the effect of a single genetic variant or
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therapeutic candidate on a genetically diverse background population in mice, an approach that would require larger, more complicated animal studies, but might improve the
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translational validity to a diverse human population.
The identification of biomarkers for biological aging could dramatically alter clinical and
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epidemiological studies as they could be used to monitor short and medium term interventional strategies. Classical biomarkers include sarcopenia17, physical frailty and
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cognitive frailty.18 Aging also impacts biological functions that are too numerous to include in their entirety in a single clinical study, thus endpoint selection will need to be well-
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informed by the underlying biological hypothesis for the treatment and the animal data generated with a therapeutic. More recently, a range of other biomarkers of aging (described below) have been developed largely using AI-based strategies exploring deep biologic
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datasets. These measures potentially permit measures of biological aging across a wider life trajectory and may be dynamic in nature, responding to interventions in a shorter timeframe. In addition, wearable devices and other objective and data-rich measurements are being tested and are likely to provide much better and cleaner assessments of the aging process, improving the quality of clinical trials and our ability to back-translate to similar
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objective endpoints in non-human species. While the best biomarkers remain a matter of debate, the development of anti-aging therapeutics can still proceed through the analysis of specific indications, at least in the short term. As age is a common risk factor for the majority of disorders, it is expected that an anti-aging therapy would either delay onset or slow the decline observed in multiple pathological conditions. Rationale to Develop Anti-Aging Therapeutics 6
Development of drugs in recent years has focused almost entirely on selectivity and specificity with a primary goal to reduce the risks of any side effects. Such an approach is highly valid when considering specific indications targeting selected organs. Aging is different; the body ages systemically, although not necessarily uniformly, and it may indeed be preferential to have broad, systemic anti-aging effects. Consideration of systemic therapies, broadly distributed targets or organ systems that can have wide impacts may be strong and viable strategies to take. Approaches of potential broad value are to modulate
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processes that are ubiquitous, systemic and that potentially have multiple impacts such as targeting the plasma proteome, cellular senescence, proteostasis and metabolic processes
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(Table 1).
In a particularly broad sense, the results of heterochronic parabiosis and plasma-transfer experiments utilize this concept to demonstrate widespread effects of a complex molecular
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mixture. These procedures effectively take a mixture of thousands of proteins present in plasma that have been identified to either accelerate or reverse aging of organs including the mechanisms
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modulating
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brain, pancreas, heart, liver and others, 16-21 These factors display a wide array of functional inflammation22,
stem
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proliferation
and
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differentiation23 and vascular benefit.24 Identification of specific blood-borne factors such as eotaxin19, GDF1120, Beta-2-microglobulin21 and TIMP225 indicate that individual factors may drive at least some of these activities and be systemic regulators of function and dysfunction,
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but also in aging the ability to modulate multiple mechanisms in a single therapeutic of plasma or a fraction of plasma could be very valuable. Another broad approach capitalizes on cellular senescence - as the body ages, cellular processes become disrupted, including an arrest in the ability of cells to proliferate and differentiate leading to their ultimate death. Dying senescent cells accumulate with aging and
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release soluble factors that can drive further age-related diseases in a paracrine or endocrine manner, the senescence associated phenotype (SASP).26 The removal of senescent cells has been demonstrated to reverse age-related deficits27 and thus modulating senescence processes or senescent cells could be an anti-aging approach. Rapamycin is one of the current prototypic anti-aging drugs and at least partly effects aging processes through modulation of proteostasis. The proteostatic systems of different cells and organs are highly interconnected at the organismal level. Cell and organ non-autonomous 7
regulation of specific proteostatic pathways has now been demonstrated in both invertebrates and mice.28 Therefore, it may be possible to target a proteostatic regulator in a peripheral organ (e.g., mTORC pathway in muscle) and have a positive impact on the CNS or vice versa.29, 30 Inter-organ communication regulating proteostasis may be mediated via soluble factors such as exosomes, which can transfer chaperones and other proteins between cells.31, 32 Studies in mice suggest it should be possible to impact systemic aging by targeting a single peripheral organ. For example, activation of 4E-BP1 (a downstream effector of
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mTORC1) specifically in muscle is sufficient to promote healthy aging across many tissues.31 Of note, rapamycin-mediated mTOR inhibition also results in partial SASP inhibition,
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improvement of adult stem cell function with age, and robust anti-inflammatory effects, which all (in addition to improved proteostasis) may contribute to its promotion of lifespan and healthspan.
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Metformin has been proposed as a broad anti-aging therapeutic through its effects on metabolic function. It is used to treat diabetes, a condition associated with accelerated aging. Epidemiological correlates of metformin treatment of elderly with type 2 diabetes with
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increased longevity have been made34 and health and lifespan of mice have been enhanced
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with the drug.35 The data with rapamycin and metformin indicate that there may be multiple means to broadly target processes in the body resulting in delayed aging, increased healthspan and longevity. Nonetheless, despite the hope from epidemiologic studies, properly
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controlled clinical trials are required to understand the specific value of both rapamycin and metformin as therapeutics for aging. Other pathways and mechanisms that have not previously been targeted can also be of great potential and thus the field can not rely on these approaches alone.
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Overcoming Translational Challenges from Animal Models to Humans The development of anti-aging drugs poses new challenges. Quantitative measures to assess change and clinical impact will be essential to evaluate the effectiveness of novel therapeutics. Although, for ultimate approval, endpoints that are indicative of improved quality of life will be necessary, the development of such therapeutics can be led by surrogate biomarkers. Several biomarkers have now been identified that distinguish biological from chronological aging in various organisms. These include composite measures of health and 8
physiological function such as the Frailty Index 34, panels of inflammatory cytokines, p16INK4A(a marker of cellular senescence), and specific patterns of DNA methylation changes.36, 37 Of these, DNA methylation changes, known as the “epigenetic clock” have been the most thoroughly studied. The clock was first identified in humans, and shown to predict future mortality and other health outcomes.36, 37 Epigenetic clocks have now been identified in mice and respond as expected to experimental interventions - for example, caloric restriction slows the clock down, whereas a high fat diet accelerates it.36-39
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The path to developing therapeutics for disease to be tested in man usually requires the use of animal models in order to define agents, their effects and their safety. The biggest risk
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factors for age-related diseases are age and time, which are the major constraints to developing animal models in both a logistically and economically feasible manner. Researchers usually use mouse models with aggressive forms of disease that develop the
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pathology of interest on an accelerated timeline. These models then lack cellular and systemic age-related factors that likely contribute to the disease. It is not cost effective or
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feasible to incorporate the time variable of normal aging so research paths bias towards abbreviated timelines. It is possible to study lower organisms with much shorter lifespans,
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but species differences and translatability are even more challenging than with mice. A start towards this would be to have extensive, pre-existing aging mouse colonies, but these still provide complexity - animals show increasing variability in their biology and health as they
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age. So, in studying age-related processes large cohorts will be required, some mice will die before the time of the intended experiment, others will develop tumors or age-related issues like blindness. Furthermore, immune systems and metabolism will change in ways we don’t fully understand yet. It becomes very difficult to do meaningful mechanistic studies if one doesn’t know whether it’s aging per se or an age-related comorbidity that is driving the
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phenotype.
A further issue in translation is that humans have more diverse genetic backgrounds and environmental exposures than experimental mice do. It is possible to increase genetic diversity in mice: for example, the NIA Interventions Testing Program uses 4-way crosses that approximate human genetic diversity.
40, 41
With respect to environmental factors, in
mouse studies it has often been difficult to replicate results from lab to lab even with identical genetic backgrounds and phenotypic assays. Similarly, in humans, environmental 9
conditions in clinical trials also vary among clinical centers and experimenters, and lifetime environmental exposures are far more diverse than in mice. Thus, it may be difficult to find a single intervention that works in everyone, but we should not be discouraged, for example ThioflavinT displays robust anti-aging effects across 22 strains of C.elegans 40 and rapamycin extends lifespan across a range of species and in multiple mouse strains. As research advances, we will understand more about the relationship between biology in preclinical
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models and man and in particular the temporal translation to help us advance therapeutics.
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What May Anti-Aging Therapeutics Look Like?
Is a golden bullet of a single drug to impact aging biology a realistic scenario? The diversity of age-related disorders, the multitude of potential endpoints, the complexities of genetic
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risk factors and environmental challenges accumulating over a lifetime all make a single therapeutic unlikely. However, if there are fundamental underlying mechanisms, such as
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cellular senescence or failure of proteostatic maintenance, or a natural mixture, such as plasma or a fraction of plasma able to modulate multiple mechanisms, then potentially a
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single therapeutic could halt, or at least delay, most age-related disorders. It is still early for us to ascertain this, but the prospect will be tested in the clinic. Non-pharmacological interventions (e.g., exercise and caloric restriction) may be more
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effective and easier to develop than pharmacological ones in the near term and certainly should be pursued aggressively. Evidence is mounting that such approaches are the most effective that we have currently against disorders such as AD and that they may act through the multimodal mechanisms that we believe are important in aging41 (Table 1). Many studies are comprehensively testing such approaches and conceptually it can often be easier to see
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how implementation for these may be, both practically and financially, much more efficient than developing a new pharmaceutical therapy. However, easy as these appear they can be difficult for people to implement – keeping exercise regimens going in the frail elderly (or even healthy adults), or embracing caloric restriction/intermittent fasting is often not a longterm solution to which most can adhere. It may be more effective to prescribe combinations of pharmacological and non-pharmacological interventions. In any event, we need to make the research and development of non-pharmacological interventions a priority to fully 10
understand their impact and underlying biological rationales. Ultimately, we may need to look at individual genetic and environmental risk factors and design a custom-tailored combination of lifestyle and pharmacological interventions. To some extent, perhaps aging is already being treated, with drugs targeted to specific diseases, such as Metformin for hyperglycemia and aspirin to reduce cardiovascular disease risk. These and a number of other drugs commonly used to treat chronic disease conditions have been found to extend lifespan in lower organisms and in mice.42, 43 It may turn out that
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the most effective treatments for chronic disease that we’ve developed over the last 30 years (e.g., metformin, statins) are ones that impact the interface between aging and disease. On
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the other hand, these drugs may not affect the aging process per se. The thorough testing of these pre-existing drugs in controlled studies specifically addressing effects on aging, such
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as the Targeting Aging with Metformin (TAME) study 44, will be particularly informative.
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Funding and Regulatory issues
Associated with the treatment of aging is a new set of interpretations of clinical success that
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go beyond purely scientific concepts. In particular, advancing a therapeutic for aging means that we have long timelines, yet to be validated outcome measures and a lack of clarity about the regulatory environment for such therapies. These challenges impact how aging
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therapeutics will be funded and considered. Nonetheless, there is an appetite by the broad community to achieve these goals and thus navigating this path is feasible and worthwhile. Private sector
Ultimately drug development is an expensive business that is driven by private organizations
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investing in the reward of eventual products. At the early stage, even before pharmaceutical companies are involved, venture capital needs to invest and is certainly drawn to the market demographics of anti-aging therapeutics – approaching a quarter of the population will be older than 60 by 2050. Indeed, a multi-billion dollar per year anti-aging industry already exists in the form of nutraceutical and cosmetic companies. The challenge will be to bring a scientific approach to the space, which rigorously delivers products that are tested and effective to people - not just marketing unproven remedies. New opportunities for 11
developing anti-aging therapeutic approaches can also come from the blurring of lines between technology and biotechnology to offer novel interventions and concepts. However, the private sector needs to explore such new areas in a capital-efficient manner: there need to be clear go/no go points for testing in a reasonable amount of time. Therefore, even if not proven as regulatory endpoints, biomarkers that can be assessed in shorter timeframes will be invaluable in keeping the pathway to therapeutics advancing effectively and ensuring that
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capital risks are evaluated during therapeutic development. Public sector
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The role of the public sector in driving this field is highly significant; pursuing combinations of basic and translational research is fundamental to how success can be achieved. The National Institutes of Health (NIH) is positioned to take some risks that the private sector
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would be less likely to engage. For example, the National Institute on Aging (NIA) is currently funding a number of studies on the potential beneficial effects of exercise on cognition, both
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during normal aging and in neurodegenerative disorders, as well as other nonpharmacological approaches, like caloric restriction. The NIA is soliciting applications for
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clinical trials for pharmaceutical and non-pharmacological interventions to treat not only AD, but the full spectrum of age-related diseases (diabetes, osteoporosis, etc.), including interventions that target multiple comorbid conditions simultaneously. Concepts such as the
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TAME trial, which will use as its endpoint “time to a new occurrence of composite outcome that includes cardiovascular events, cancer, dementia, and mortality”44, are also indicative of the sort of innovative, commercially challenging approach that the NIH can help drive. NIH funds and partners with industry as well as academia. For example, the Accelerating Medicines Program (AMP) is a collaborative research program co-funded by the NIH, 10
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biotechnology companies and 12 non-profit disease foundations. AMP’s goal is to identify and validate new drug targets (with an initial focus on AD, type II diabetes, and rheumatoid arthritis/lupus), making data and analyses from the participating projects freely available in a public database. Both the NIH and the National Science Foundation (NSF) also fund biotechnology companies directly through their Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) grant programs. Aging is not just a domain of interest in the US, funding agencies worldwide are keenly supporting advancement in this 12
area as the whole world’s population is aging and the value of such broad approaches are evident. Partnerships between public and private sectors may be the most effective way to drive this field forward; with willingness and passion across all areas, we will have the best opportunities to successfully advance. Regulatory and Clinical Trials Issues
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Regulatory issues pose some hurdles to the development of anti-aging therapeutics, but with a common goal in mind these can be navigated. Firstly, the FDA requires clinical trial
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endpoints be related to specifically impacting health or quality of life - survival, function, or feeling, not biomarkers. This must be kept in mind as we develop drugs, although biomarkers are going to be critical in assessing efficacy especially over extended time periods, they will
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not by themselves be sufficient for approval. Secondly, payers require a specific disease code for patient reimbursement, these will need much consideration as we move concepts from
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targeting specific indications to generalizing age-related diseases. These areas, which can be
Conclusions
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resolved by working together, should not be left too late for consideration.
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We are at an exciting juncture where the realities of anti-aging therapies are upon us, and discussing how we can practically advance such approaches is a necessity. Even though a majority of research and therapeutic development focuses on individual domains such as neuroscience or behavior alone, thinking in the context of a systemic impact as we age provides wholly new opportunities, not only to tackle neurological disorders, but a spectrum
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of age-related ailments. The involvement of multiple disciplines, perspectives and constituents in the field will be needed to be successful. This collaborative approach must be triggered so that quality of life for all can be improved in the near future. Acknowledgements The authors thank Gabrielle LeBlanc (Leblanc Bioscience Consulting, Berkeley, CA) for help in writing the manuscript. This review is based in part on an open scientific satellite 13
symposium titled “Aging: Therapeutics for a Healthy Future” held in conjunction with the 46th Annual Society for Neuroscience meeting in 2016, sponsored and organized by Charles River Laboratories. The meeting panelists included: Robert Hodgson (CNS Biology, Takeda, San Diego CA), Brian K. Kennedy (Yong Loo Lin School of Medicine, National University of Singapore, Buck Institute for Research on Ageing) , Eliezer Masliah (National Institute of Aging), Kimberly Scearce-Levie (Denali Therapeutics), Barbara Tate
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(Dementia Discovery Fund) and Steven P. Braithwaite (Alkahest Inc, San Carlos, CA).
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REFERENCES [1] Khan SS, Singer BD, Vaughan DE. Molecular and physiological manifestations and measurement of aging in humans. Aging Cell. 2017; Aug;16(4):624-633. doi: 10.1111/acel.12601 . [2] Soto-Gamez A, Demaria M. Therapeutic interventions for aging: The case of cellular senescence. Drug discovery today. 2017;22:786-795
of
[3] Erikson GA, Bodian DL, Rueda M, Molparia B, Scott ER, Scott-Van Zeeland AA, et al. Whole-genome sequencing of a healthy aging cohort. Cell. 2016;165:1002-1011
ro
[4] Niccoli T, Partridge L. Ageing as a risk factor for disease. Curr Biol. 2012;Sep 11;22(17):R741-52. doi: 10.1016/j.cub.2012.07.024.
[5] Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, et al. Geroscience:
-p
Linking aging to chronic disease. Cell. 2014;159:709-713 aging. Cell. 2013;153:1194-1217
re
[6] Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of [7] Pan H, Finkel T. Key proteins and pathways that regulate lifespan. The Journal of
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biological chemistry. 2017;292:6452-6460
[8] Gao AW, Uit de Bos J, Sterken MG, Kammenga JE, Smith RL, Houtkooper RH. Forward and reverse genetics approaches to uncover metabolic aging pathways in
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Caenorhaditis elegans. Biochim Biophys Acta. 2017; pii:S0925-4439 (17) 30321-6. [9] Bitto A, Wang AM, Bennett CF, Kaeberlein M. Biochemical Genetics Pathways that Modulate Aging in Multiple Species. Cold Spring Harb Perspect Med. 2015; 5(11): pii:a025114
[10] Gladyshev VN. Aging: Progressive decline in fitness due to the rising deleteriome
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adjusted by genetic, environmental, and stochastic processes. Aging cell. 2016;15:594-602 [11] Lucanic M, Plummer WT, Chen E, Harke J, Foulger AC, Onken B, et al. Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects. Nature communications. 2017;8:14256 [12] Wyss-Coray T. Ageing, neurodegeneration and brain rejuvenation. Nature. 2016;539:180-186 15
[13] Podtelezhnikov AA, Tanis KQ, Nebozhyn M, Ray WJ, Stone DJ, Loboda AP. Molecular insights into the pathogenesis of alzheimer's disease and its relationship to normal aging. PloS one. 2011;6:e29610 [14] Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 2011; 477
of
(7362):90-4 doi: 10.1038/nature10357 [15] Vaiserman A, Lushchak O. Implementation of longevity-promoting supplements
ro
and medications in public health practice: achievements, challenges and future
perspectives. J Transl Med. 2017; Jul 20;15(1):160. doi: 10.1186/s12967-017-12598.
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[16] Kõks S, Dogan S, Guvenc Tuna B, González-Navarro H, Potter P, Randenbroucke RE.
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[17] Mouse models of ageing and their relevance to disease. Mechanisms of Ageing and Development 2016; 160: 41-53
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[18] Kalinkovich A, Livshits G. Sarcopenia- The search for emerging biomarkers. Ageing Res Rev 2015; 22:58-71 doi: 10.1016/j.arr.2015.05.001 [19] Ruan Q, D'Onofrio G, Sancarlo D, Greco A, Lozupone M, Seripa D, Panza F, Yu Z.
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Emerging biomarkers and screening for cognitive frailty. 2017 Aging Clin Exp Res 29(6):1075-1086. doi: 10.1007/s40520-017-0741-8 [20] Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 2014 May 9;344(6184):630-4.
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doi: 10.1126/science.1251141 [21] Helman A, Avrahami D, Klochendler A, Glaser B, Kaestner KH, Ben-Porath I, Dor Y. Effects of ageing and senescence on pancreatic β-cell function. Diabetes Obesity and Metabolism. 2016 Sep;18 Suppl 1:58-62. doi: 10.1111/dom.12719 [22] Smith LK, He Y, Park JS, Bieri G, Snethlage CE, Lin K, Gontier G, Wabl R, Plambeck KE, Udeochu J, Wheatley EG, Bouchard J, Eggel A, Narasimha R, Grant JL, Luo J, WyssCoray T, Villeda SA. β2-microglobulin is a systemic pro-aging factor that impairs 16
cognitive function and neurogenesis. Nature Medicine. 2015 Aug;21(8):932-7. doi: 10.1038/nm.3898 [23] Sallam N, Laher I. Exercise Modulates Oxidative Stress and Inflammation in Aging and Cardiovascular Diseases. Oxid Med Cell Longev.2016; 2016:7239639. doi: 10.1155/2016/7239639. [24] Ahmed AS, Sheng MH, Wasnik S, Baylink DJ, Lau KW. Effect of aging on stem cells. World J Exp Med. 2017 Feb 20;7(1):1-10. doi: 10.5493/wjem.v7.i1.1. hypertension. J Mol Cell Cardiol. 2015; Jun;83:112-21. doi:
ro
10.1016/j.yjmcc.2015.04.011.
of
[25] Harvey A, Montezano AC, Touyz RM. Vascular biology of ageing-Implications in
[26] Castellano JM, Mosher KI, Abbey RJ, McBride AA, James ML, Berdnik D, Shen JC, Zou B, Xie XS, Tingle M, Hinkson IV, Angst MS, Wyss-Coray T. Human umbilical cord
-p
plasma proteins revitalize hippocampal function in aged mice. Nature 2017 Apr 27;544(7651):488-492. doi: 10.1038/nature22067
re
[27] Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015; Dec;21(12):1424-
lP
35. doi: 10.1038/nm.4000.
[28] Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays
ur na
ageing-associated disorders. Nature. 2011; Nov 2;479(7372):232-6. doi: 10.1038/nature10600.
[29] Sala AJ, Bott LC, Morimoto RI. Shaping proteostasis at the cellular, tissue, and organismal level. The Journal of cell biology. 2017;216:1231-1241. [30] Dubinsky AN, Dastidar SG, Hsu CL, Zahra R, Djakovic SN, Duarte S, et al. Let-7
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coordinately suppresses components of the amino acid sensing pathway to repress mtorc1 and induce autophagy. Cell metabolism. 2014;20:626-638 [31] Williams KW, Liu T, Kong X, Fukuda M, Deng Y, Berglund ED, et al. Xbp1s in pomc neurons connects er stress with energy balance and glucose homeostasis. Cell metabolism. 2014;20:471-482
17
[32] Tsai S, Sitzmann JM, Dastidar SG, Rodriguez AA, Vu SL, McDonald CE, et al. Muscle-specific 4e-bp1 signaling activation improves metabolic parameters during aging and obesity. The Journal of clinical investigation. 2015;125:2952-2964 [33] Kaushik S, Cuervo AM. Proteostasis and aging. Nature medicine. 2015;21:14061415 [34] McDaniel CF. Diabetes: A model of oxidative accelerated aging. Age (Omaha). 1999; Oct;22(4):145-8. doi: 10.1007/s11357-999-0016-1.
of
[35] Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox, JP, Schernthaner G, Mukherjee J, Currie CJ. Can people with type 2 diabetes live longer than those
ro
without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab. 2014; Nov;16(11):1165-73. doi: 10.1111/dom.12354.
-p
[36] Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, ScheibyeKnudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y,
re
Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;
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4:2192. doi: 10.1038/ncomms3192.
[37] Chen BH, Marioni RE, Colicino E, Peters MJ, Ward-Caviness CK, Tsai PC, et al. DNA methylation-based measures of biological age: Meta-analysis predicting time to
ur na
death. Aging. 2016;8:1844-1865
[38] Horvath S. DNA methylation age of human tissues and cell types. Genome biology. 2013;14:R115
[39] Wagner W. Epigenetic aging clocks in mice and men. Genome biology. 2017;18:107
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[40] Stubbs TM, Bonder MJ, Stark AK, Krueger F, Team BIAC, von Meyenn F, et al. Multi-tissue DNA methylation age predictor in mouse. Genome biology. 2017;18:68 [41] Lucanic M, Plummer WT, Chen E, Harke J, Foulger AC, Onken B, et al. Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects. Nature communications. 2017;8:14256 [42] Nadon NL, Strong R, Miller RA, Nelson J, Javors M, Sharp ZD, et al. Design of aging intervention studies: The nia interventions testing program. Age. 2008;30:187-199 18
[43] Newman JC, Milman S, Hashmi SK, Austad SN, Kirkland JL, Halter JB, et al. Strategies and challenges in clinical trials targeting human aging. The journals of gerontology. Series A, Biological sciences and medical sciences. 2016;71:1424-1434 [44] Blagosklonny MV. From rapalogs to anti-aging formula. Oncotarget. 2017;8:35492-35507 [45] Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell metabolism. 2016;23:1060-106
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[46] Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine.
ro
2018;36:18-28.
[47] Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat
-p
Med. 2016;22:78–83.
[48] Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, et al. Senolytic
re
therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model. Nat Neurosci. 2019;22(5):719-728.
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[49] Lamming DW, Ye L, Sabatini DM, Baur JA. Rapalogs and mTOR inhibitors as antiaging therapeutics. J Clin Invest. 2013;123(3):980-9. [50] Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene
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leads to a syndrome resembling ageing. Nature. 1997;390(6655):45–51 [51] Sha SJ, Deutsch GK, Tian L, Richardson K, Coburn M et al. Safety, Tolerability, and Feasibility of Young Plasma Infusion in the Plasma for Alzheimer Symptom Amelioration Study: A Randomized Clinical Trial. JAMA Neurol. 2019;76(1):35-40. [52] Kheifets V, Braithwaite SP. Plasma-Based Strategies for Therapeutic Modulation
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of Brain Aging. Neurotherapeutics. 2019;16(3):675-684. [53] Brooks RW, Robbins PD. Treating Age-Related Diseases with Somatic Stem Cells. Adv Exp Med Biol. 2018;1056:29-45. [54] Tamanini S, Comi GP, Corti S. In Vivo Transient and Partial Cell Reprogramming to Pluripotency as a Therapeutic Tool for Neurodegenerative Diseases. Mol Neurobiol. 2018;55(8):6850-6862.
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[55] Shay JW, Wright WE. Telomeres and telomerase: three decades of progress. Nat Rev Genet. 2019;20(5):299-309. [56] Michan S. Calorie restriction and NAD⁺/sirtuin counteract the hallmarks of aging. Front Biosci 2014;19:1300-19. [57] Anton S, Leeuwenburgh C. Fasting or caloric restriction for healthy aging. Exp Gerontol. 2013;48(10):1003-5. [58] Kivipelto M, Mangialasche F, Ngandu T. Lifestyle interventions to prevent
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cognitive impairment, dementia and Alzheimer disease. Nat Rev Neurol. 2018;14(11):653-666.
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[59] Kramer AF, Erickson KI, Colcombe SJ. Exercise, cognition, and the aging brain. J Appl Physiol 2006;101:1237-1242.
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Figure 1: The brain and peripheral organs share common biological mechanisms of aging. The well described pillars of aging6 are evident systemically, linking the neurological and behavioral consequences of aging and peripheral organs whose function also declines with age. A strong hope for therapeutics of aging is that a cross-therapeutic area benefit will be achieved
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Table 1: Key therapeutic strategies for aging biology Therapeutic Candidates
48 49 19, 21, 50, 51 52 53 54 55
55,56, 57 57, 58
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Multiple regimens Multiple regimens
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Non-Pharmacological Caloric Restriction Exercise
44 45, 46, 47
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Metformin (Biguanides) Fisetin, Bcl2 inhibitors, Dasatinib, Quecertin Proteostasis/autophagy Rapamycin, Rapalogs Nutrient Sensing Klotho Intercellular signaling Plasma, Plasma Fractions, GDF11 Stem cell exhaustion Mesenchymal stem cells Epigenetic Yamanaka factors reprogramming Telomere shortening Telomerase Genomic Instability NAD+
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Pharmacological Metabolic function Cellular Senescence
References
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Process
PII:
S0149-7634(19)30134-4
DOI:
https://doi.org/10.1016/j.neubiorev.2019.11.021
Reference:
NBR 3609
To appear in:
Neuroscience and Biobehavioral Reviews
Received Date:
13 February 2019
Revised Date:
22 September 2019
Accepted Date:
25 November 2019
Please cite this article as: Hodgson R, Kennedy BK, Masliah E, Scearce-Levie K, Tate B, Venkateswaran A, Braithwaite SP, AGING: THERAPEUTICS FOR A HEALTHY FUTURE, Neuroscience and Biobehavioral Reviews (2019), doi: https://doi.org/10.1016/j.neubiorev.2019.11.021
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
AGING: THERAPEUTICS FOR A HEALTHY FUTURE Running title: Aging Therapeutics Robert Hodgson1, 2, Brian K. Kennedy3, 4, Eliezer Masliah5, Kimberly Scearce-Levie6, Barbara Tate7, Anjli Venkateswaran2, Steven P. Braithwaite8 1Charles
River Laboratories, Wilmington, MA, Biology, Takeda San Diego, CA, 3Departments of Biochemistry and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 4Buck Institute for Research on Ageing, 5National Institute of Aging , 6Denali Therapeutics, 7Dementia Discovery Fund, 7, 8Alkahest Inc, San Carlos, CA
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Corresponding Author: Steven P. Braithwaite, Alkahest Inc. 125 Shoreway Road, Suite D, San
Approaching aging as a target is a new therapeutic frontier Potential of modifying aging processes can be transformative for medicine Multiple mechanisms have the potential to deliver improvements in healthspan Challenges of science, translation, economics and regulation need to be navigated Encouragement from collaboration between academia, industry, funders and regulators
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Highlights
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Carlos CA, 94070. Phone: +1-650-801-0470; Email: [email protected]
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Abstract
Increased healthcare and pharmaceutical understanding has led to the eradication of many childhood, infectious and preventable diseases; however, we are now experiencing the impact of aging disorders as the lifespan increases. These disorders have already become a major burden on society and threaten to become a defining challenge of our generation. Indications such as Alzheimer’s disease gain headlines and have focused the thinking of 1
many towards dementia and cognitive decline in aging. Indications related to neurological function and related behaviors are thus an extremely important starting point in the consideration of therapeutics. However, the reality is that pathological aging covers a spectrum of significant neurological and peripheral indications. Development of therapeutics to treat aging and age-related disorders is therefore a huge need, but represents a largely unexplored path.
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Fundamental scientific questions need to be considered as we embark towards a goal of improving health in old age, including how we 1) define aging as a therapeutic target, 2)
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model aging preclinically and 3) effectively translate from preclinical models to man. Furthermore, the challenges associated with identifying novel therapeutics in a financial, regulatory and clinical sense need to be contemplated carefully to ensure we address the
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unmet need in our increasingly elderly population. The complexity of the challenge requires different perspectives, cross-functional partnerships and diverse concepts. We seek to raise
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issues to guide the field, considering the current state of thinking to aid in identifying roadblocks and important challenges early. The need for therapeutics that address aging and
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age-related disorders is acute, but the promise of effective treatments provides huge opportunities that, as a community, we all seek to enable effectively as soon as possible.
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Keywords: Aging, neurodegeneration, review, longevity, healthspan
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Aging – What Are We Attempting to Treat? Many consider aging as a purely chronological phenomenon; it is an immutable fact that we all get older. However, this is a simplification as individuals all age functionally in different ways and the concept of “biological aging” is more relevant than chronological aging.1 When we consider biological aging, we have a therapeutic target, not simply targeting getting old, rather treating physiological decline that is manifested by dysfunction and morbidity in late
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life. When biological aging becomes pathological, it can be considered as a failure of homeostasis. There is a progressive component, but ultimately a point is reached at which
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there is inability to counter the amassed toll on the body of time-dependent accumulation of cellular damage (DNA mutations, protein misfolding, oxidative stress etc.), which occurs throughout life. With age, cellular processes (including stress response pathways invoked
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by damage) become less efficient, ultimately leading to cellular death and irreversible consequences. At younger ages, the body is able to mount compensatory responses and life
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is healthy. During middle age, the body’s ability to maintain homeostasis declines, resulting in chronic diseases that accelerate the gradual degradation of life quality, resulting in severe
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detriments, frailty and, eventually, mortality. There are many ways that a homeostatic balance can be maintained, giving many opportunities for development of therapeutics.
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When considering therapeutic outcomes, it is also important to consider the primary goal. Lifespan extension is an obvious target, but controversially there may be a maximum lifespan 2 and, more importantly, long life with low quality of life may be even less desirable. Instead, the concept of improving healthspan, the time of life in which we are healthy, is more realistic and one that many aspire to – being healthy in old age - whether or not this also
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leads to a longer life. The pathways modulating lifespan and healthspan are likely overlapping but distinct. Many interventions extend both in animal models, but different genes have also been associated with longevity versus disease-free aging in human studies.3 Age is a major risk factor for many chronic diseases, including those with huge impact on individuals and society such as Alzheimer’s disease (AD), cancer, cardiovascular disease, and diabetes.4 Aging is also a complex, multifactorial process. Key “pillars” or processes of aging 3
have been identified, including inflammation, macromolecular damage, and breakdown of proteostasis, epigenetic changes, and accumulation of senescent cells.5, 6 These pillars of aging link organ systems too, the brain clearly impacted by neuroinflammation, deficits in proteostasis leading to accumulation of aggregate-prone proteins and loss of stem cells in key areas involved in memory formation. Also in the periphery, from bone to skin to core organs, the biology of aging has widespread impact (Figure 1). These mechanistic processes are also highly intertwined, so that perturbation of one process can ramify throughout the whole
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system. This complexity and interdependence could lead to the inability to impact the system by intervening with the targeting of only one gene or with one single drug. However, it seems
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likely that a single event or small number of events can push “normal” aging over the edge into chronic disease. Thus, specific genetic mutations and single drugs can increase lifespan, including rapamycin and sirtuin-activating compounds7 across a range of animal models
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including C. elegans, D. melanogaster and M. musculus.8, 9
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There is still a lot that we don’t know about aging, with organisms within a species often showing considerable variability in both lifespan and healthspan. For example, some older
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people maintain good cognitive function throughout age, even as centenarians, whereas others develop dementia in middle age. This variability is due to stochastic as well as genetic and environmental factors; even isogenic individuals of a single species (C. elegans or M.
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musculus) raised in the same environment show wide differences in lifespans and ages of onset of degenerative pathologies.10-12 Understanding why these differences occur and how they contribute to pathological aging is an essential to guide the development of novel therapeutics. We also need to understand if there are mechanistic differences between normal and pathological biological aging, or if pathological aging is just accelerated biological
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aging. Likely, it is a combination, with these complex disorders of old age being an accumulation of multiple disease specific risk factors, environmental exposures and aging processes, where modifying even one component prior to overt disease may be able to alter the onset and/or course of multiple diseases.
13, 14
Attractively, if you can delay negative
aging processes, keeping people healthier as they age, an array of serious age-related disorders could be prevented. It is clear that increased understanding of the biology of aging can lead to wholly new therapeutic approaches of great potential impact. 4
Issues Involved in Developing Anti-Aging Therapies A therapeutic that halts or prevents aging, putting off the onset of a debilitating disorder, could lead to a longer life. Extending life on the face of it is highly positive; the vast majority of the population looks forward to a long and fruitful life. However, if anti-aging therapies only increase lifespan without increasing healthspan it will just increase the population of diseased elderly, increasing healthcare spending and providing an undesirable,
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unsustainable, future for society. If healthspan is increased, thus delaying the onset of an array of age-related disorders there could be a highly positive societal and economic impact.
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People could work longer, contribute more economically and have a more positive, productive life with a concomitant reduction in chronic health-related disorders. This would potentially lead to later retirement (an event likely to happen anyway with the aging of the
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population), and changes in population distribution, as longer lifespan correlates with reduced populations. The ethical implications must always be kept in mind, but the
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advantages and impacts of developing anti-aging drugs to improve the quality of life in old
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age are highly significant.15
Multiple Challenges of Developing Anti-Aging Therapeutics With the lofty goal to counteract aging, development of novel therapeutics will encounter a
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series of challenges, many of which have little or no precedent in prior clinical efforts. In particular, it is not clear how to design a clinical trial to assess strategies to slow the progression of aging per se. For diseases with a degenerative component, such as AD, trials often last many years, which is necessary to observe therapeutic effect over a slow rate of neurodegenerative decline. Independent of neurodegenerative disease, the rate of purely
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age-related decline may even be slower, and more variable between individuals, likely requiring even larger trials of longer duration. Moreover, therapies that require intervention earlier, in pre-symptomatic states, will require trials of extremely long duration, uncertain outcome and include immense heterogeneity. Designs will be based on outcomes of animal studies, where the aging time course differs dramatically from human aging and is likely different in many ways.
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Mouse models will be critical to identify new links between aging and disease, but it is important to note that while inbred mouse strains are likely to have relatively more homogeneous cohorts, outbred mice that are more representative of aging in human populations show more variation in aging processes. 16 Thus, how rodent outcomes translate to human trials remains unclear and the question of when it is best to start an intervention will be to an extent empirical from multiple human studies. New approaches to animal model development can allow researchers to evaluate the effect of a single genetic variant or
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therapeutic candidate on a genetically diverse background population in mice, an approach that would require larger, more complicated animal studies, but might improve the
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translational validity to a diverse human population.
The identification of biomarkers for biological aging could dramatically alter clinical and
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epidemiological studies as they could be used to monitor short and medium term interventional strategies. Classical biomarkers include sarcopenia17, physical frailty and
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cognitive frailty.18 Aging also impacts biological functions that are too numerous to include in their entirety in a single clinical study, thus endpoint selection will need to be well-
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informed by the underlying biological hypothesis for the treatment and the animal data generated with a therapeutic. More recently, a range of other biomarkers of aging (described below) have been developed largely using AI-based strategies exploring deep biologic
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datasets. These measures potentially permit measures of biological aging across a wider life trajectory and may be dynamic in nature, responding to interventions in a shorter timeframe. In addition, wearable devices and other objective and data-rich measurements are being tested and are likely to provide much better and cleaner assessments of the aging process, improving the quality of clinical trials and our ability to back-translate to similar
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objective endpoints in non-human species. While the best biomarkers remain a matter of debate, the development of anti-aging therapeutics can still proceed through the analysis of specific indications, at least in the short term. As age is a common risk factor for the majority of disorders, it is expected that an anti-aging therapy would either delay onset or slow the decline observed in multiple pathological conditions. Rationale to Develop Anti-Aging Therapeutics 6
Development of drugs in recent years has focused almost entirely on selectivity and specificity with a primary goal to reduce the risks of any side effects. Such an approach is highly valid when considering specific indications targeting selected organs. Aging is different; the body ages systemically, although not necessarily uniformly, and it may indeed be preferential to have broad, systemic anti-aging effects. Consideration of systemic therapies, broadly distributed targets or organ systems that can have wide impacts may be strong and viable strategies to take. Approaches of potential broad value are to modulate
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processes that are ubiquitous, systemic and that potentially have multiple impacts such as targeting the plasma proteome, cellular senescence, proteostasis and metabolic processes
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(Table 1).
In a particularly broad sense, the results of heterochronic parabiosis and plasma-transfer experiments utilize this concept to demonstrate widespread effects of a complex molecular
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mixture. These procedures effectively take a mixture of thousands of proteins present in plasma that have been identified to either accelerate or reverse aging of organs including the mechanisms
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modulating
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brain, pancreas, heart, liver and others, 16-21 These factors display a wide array of functional inflammation22,
stem
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proliferation
and
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differentiation23 and vascular benefit.24 Identification of specific blood-borne factors such as eotaxin19, GDF1120, Beta-2-microglobulin21 and TIMP225 indicate that individual factors may drive at least some of these activities and be systemic regulators of function and dysfunction,
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but also in aging the ability to modulate multiple mechanisms in a single therapeutic of plasma or a fraction of plasma could be very valuable. Another broad approach capitalizes on cellular senescence - as the body ages, cellular processes become disrupted, including an arrest in the ability of cells to proliferate and differentiate leading to their ultimate death. Dying senescent cells accumulate with aging and
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release soluble factors that can drive further age-related diseases in a paracrine or endocrine manner, the senescence associated phenotype (SASP).26 The removal of senescent cells has been demonstrated to reverse age-related deficits27 and thus modulating senescence processes or senescent cells could be an anti-aging approach. Rapamycin is one of the current prototypic anti-aging drugs and at least partly effects aging processes through modulation of proteostasis. The proteostatic systems of different cells and organs are highly interconnected at the organismal level. Cell and organ non-autonomous 7
regulation of specific proteostatic pathways has now been demonstrated in both invertebrates and mice.28 Therefore, it may be possible to target a proteostatic regulator in a peripheral organ (e.g., mTORC pathway in muscle) and have a positive impact on the CNS or vice versa.29, 30 Inter-organ communication regulating proteostasis may be mediated via soluble factors such as exosomes, which can transfer chaperones and other proteins between cells.31, 32 Studies in mice suggest it should be possible to impact systemic aging by targeting a single peripheral organ. For example, activation of 4E-BP1 (a downstream effector of
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mTORC1) specifically in muscle is sufficient to promote healthy aging across many tissues.31 Of note, rapamycin-mediated mTOR inhibition also results in partial SASP inhibition,
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improvement of adult stem cell function with age, and robust anti-inflammatory effects, which all (in addition to improved proteostasis) may contribute to its promotion of lifespan and healthspan.
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Metformin has been proposed as a broad anti-aging therapeutic through its effects on metabolic function. It is used to treat diabetes, a condition associated with accelerated aging. Epidemiological correlates of metformin treatment of elderly with type 2 diabetes with
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increased longevity have been made34 and health and lifespan of mice have been enhanced
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with the drug.35 The data with rapamycin and metformin indicate that there may be multiple means to broadly target processes in the body resulting in delayed aging, increased healthspan and longevity. Nonetheless, despite the hope from epidemiologic studies, properly
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controlled clinical trials are required to understand the specific value of both rapamycin and metformin as therapeutics for aging. Other pathways and mechanisms that have not previously been targeted can also be of great potential and thus the field can not rely on these approaches alone.
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Overcoming Translational Challenges from Animal Models to Humans The development of anti-aging drugs poses new challenges. Quantitative measures to assess change and clinical impact will be essential to evaluate the effectiveness of novel therapeutics. Although, for ultimate approval, endpoints that are indicative of improved quality of life will be necessary, the development of such therapeutics can be led by surrogate biomarkers. Several biomarkers have now been identified that distinguish biological from chronological aging in various organisms. These include composite measures of health and 8
physiological function such as the Frailty Index 34, panels of inflammatory cytokines, p16INK4A(a marker of cellular senescence), and specific patterns of DNA methylation changes.36, 37 Of these, DNA methylation changes, known as the “epigenetic clock” have been the most thoroughly studied. The clock was first identified in humans, and shown to predict future mortality and other health outcomes.36, 37 Epigenetic clocks have now been identified in mice and respond as expected to experimental interventions - for example, caloric restriction slows the clock down, whereas a high fat diet accelerates it.36-39
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The path to developing therapeutics for disease to be tested in man usually requires the use of animal models in order to define agents, their effects and their safety. The biggest risk
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factors for age-related diseases are age and time, which are the major constraints to developing animal models in both a logistically and economically feasible manner. Researchers usually use mouse models with aggressive forms of disease that develop the
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pathology of interest on an accelerated timeline. These models then lack cellular and systemic age-related factors that likely contribute to the disease. It is not cost effective or
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feasible to incorporate the time variable of normal aging so research paths bias towards abbreviated timelines. It is possible to study lower organisms with much shorter lifespans,
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but species differences and translatability are even more challenging than with mice. A start towards this would be to have extensive, pre-existing aging mouse colonies, but these still provide complexity - animals show increasing variability in their biology and health as they
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age. So, in studying age-related processes large cohorts will be required, some mice will die before the time of the intended experiment, others will develop tumors or age-related issues like blindness. Furthermore, immune systems and metabolism will change in ways we don’t fully understand yet. It becomes very difficult to do meaningful mechanistic studies if one doesn’t know whether it’s aging per se or an age-related comorbidity that is driving the
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phenotype.
A further issue in translation is that humans have more diverse genetic backgrounds and environmental exposures than experimental mice do. It is possible to increase genetic diversity in mice: for example, the NIA Interventions Testing Program uses 4-way crosses that approximate human genetic diversity.
40, 41
With respect to environmental factors, in
mouse studies it has often been difficult to replicate results from lab to lab even with identical genetic backgrounds and phenotypic assays. Similarly, in humans, environmental 9
conditions in clinical trials also vary among clinical centers and experimenters, and lifetime environmental exposures are far more diverse than in mice. Thus, it may be difficult to find a single intervention that works in everyone, but we should not be discouraged, for example ThioflavinT displays robust anti-aging effects across 22 strains of C.elegans 40 and rapamycin extends lifespan across a range of species and in multiple mouse strains. As research advances, we will understand more about the relationship between biology in preclinical
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models and man and in particular the temporal translation to help us advance therapeutics.
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What May Anti-Aging Therapeutics Look Like?
Is a golden bullet of a single drug to impact aging biology a realistic scenario? The diversity of age-related disorders, the multitude of potential endpoints, the complexities of genetic
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risk factors and environmental challenges accumulating over a lifetime all make a single therapeutic unlikely. However, if there are fundamental underlying mechanisms, such as
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cellular senescence or failure of proteostatic maintenance, or a natural mixture, such as plasma or a fraction of plasma able to modulate multiple mechanisms, then potentially a
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single therapeutic could halt, or at least delay, most age-related disorders. It is still early for us to ascertain this, but the prospect will be tested in the clinic. Non-pharmacological interventions (e.g., exercise and caloric restriction) may be more
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effective and easier to develop than pharmacological ones in the near term and certainly should be pursued aggressively. Evidence is mounting that such approaches are the most effective that we have currently against disorders such as AD and that they may act through the multimodal mechanisms that we believe are important in aging41 (Table 1). Many studies are comprehensively testing such approaches and conceptually it can often be easier to see
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how implementation for these may be, both practically and financially, much more efficient than developing a new pharmaceutical therapy. However, easy as these appear they can be difficult for people to implement – keeping exercise regimens going in the frail elderly (or even healthy adults), or embracing caloric restriction/intermittent fasting is often not a longterm solution to which most can adhere. It may be more effective to prescribe combinations of pharmacological and non-pharmacological interventions. In any event, we need to make the research and development of non-pharmacological interventions a priority to fully 10
understand their impact and underlying biological rationales. Ultimately, we may need to look at individual genetic and environmental risk factors and design a custom-tailored combination of lifestyle and pharmacological interventions. To some extent, perhaps aging is already being treated, with drugs targeted to specific diseases, such as Metformin for hyperglycemia and aspirin to reduce cardiovascular disease risk. These and a number of other drugs commonly used to treat chronic disease conditions have been found to extend lifespan in lower organisms and in mice.42, 43 It may turn out that
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the most effective treatments for chronic disease that we’ve developed over the last 30 years (e.g., metformin, statins) are ones that impact the interface between aging and disease. On
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the other hand, these drugs may not affect the aging process per se. The thorough testing of these pre-existing drugs in controlled studies specifically addressing effects on aging, such
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as the Targeting Aging with Metformin (TAME) study 44, will be particularly informative.
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Funding and Regulatory issues
Associated with the treatment of aging is a new set of interpretations of clinical success that
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go beyond purely scientific concepts. In particular, advancing a therapeutic for aging means that we have long timelines, yet to be validated outcome measures and a lack of clarity about the regulatory environment for such therapies. These challenges impact how aging
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therapeutics will be funded and considered. Nonetheless, there is an appetite by the broad community to achieve these goals and thus navigating this path is feasible and worthwhile. Private sector
Ultimately drug development is an expensive business that is driven by private organizations
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investing in the reward of eventual products. At the early stage, even before pharmaceutical companies are involved, venture capital needs to invest and is certainly drawn to the market demographics of anti-aging therapeutics – approaching a quarter of the population will be older than 60 by 2050. Indeed, a multi-billion dollar per year anti-aging industry already exists in the form of nutraceutical and cosmetic companies. The challenge will be to bring a scientific approach to the space, which rigorously delivers products that are tested and effective to people - not just marketing unproven remedies. New opportunities for 11
developing anti-aging therapeutic approaches can also come from the blurring of lines between technology and biotechnology to offer novel interventions and concepts. However, the private sector needs to explore such new areas in a capital-efficient manner: there need to be clear go/no go points for testing in a reasonable amount of time. Therefore, even if not proven as regulatory endpoints, biomarkers that can be assessed in shorter timeframes will be invaluable in keeping the pathway to therapeutics advancing effectively and ensuring that
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capital risks are evaluated during therapeutic development. Public sector
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The role of the public sector in driving this field is highly significant; pursuing combinations of basic and translational research is fundamental to how success can be achieved. The National Institutes of Health (NIH) is positioned to take some risks that the private sector
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would be less likely to engage. For example, the National Institute on Aging (NIA) is currently funding a number of studies on the potential beneficial effects of exercise on cognition, both
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during normal aging and in neurodegenerative disorders, as well as other nonpharmacological approaches, like caloric restriction. The NIA is soliciting applications for
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clinical trials for pharmaceutical and non-pharmacological interventions to treat not only AD, but the full spectrum of age-related diseases (diabetes, osteoporosis, etc.), including interventions that target multiple comorbid conditions simultaneously. Concepts such as the
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TAME trial, which will use as its endpoint “time to a new occurrence of composite outcome that includes cardiovascular events, cancer, dementia, and mortality”44, are also indicative of the sort of innovative, commercially challenging approach that the NIH can help drive. NIH funds and partners with industry as well as academia. For example, the Accelerating Medicines Program (AMP) is a collaborative research program co-funded by the NIH, 10
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biotechnology companies and 12 non-profit disease foundations. AMP’s goal is to identify and validate new drug targets (with an initial focus on AD, type II diabetes, and rheumatoid arthritis/lupus), making data and analyses from the participating projects freely available in a public database. Both the NIH and the National Science Foundation (NSF) also fund biotechnology companies directly through their Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) grant programs. Aging is not just a domain of interest in the US, funding agencies worldwide are keenly supporting advancement in this 12
area as the whole world’s population is aging and the value of such broad approaches are evident. Partnerships between public and private sectors may be the most effective way to drive this field forward; with willingness and passion across all areas, we will have the best opportunities to successfully advance. Regulatory and Clinical Trials Issues
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Regulatory issues pose some hurdles to the development of anti-aging therapeutics, but with a common goal in mind these can be navigated. Firstly, the FDA requires clinical trial
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endpoints be related to specifically impacting health or quality of life - survival, function, or feeling, not biomarkers. This must be kept in mind as we develop drugs, although biomarkers are going to be critical in assessing efficacy especially over extended time periods, they will
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not by themselves be sufficient for approval. Secondly, payers require a specific disease code for patient reimbursement, these will need much consideration as we move concepts from
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targeting specific indications to generalizing age-related diseases. These areas, which can be
Conclusions
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resolved by working together, should not be left too late for consideration.
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We are at an exciting juncture where the realities of anti-aging therapies are upon us, and discussing how we can practically advance such approaches is a necessity. Even though a majority of research and therapeutic development focuses on individual domains such as neuroscience or behavior alone, thinking in the context of a systemic impact as we age provides wholly new opportunities, not only to tackle neurological disorders, but a spectrum
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of age-related ailments. The involvement of multiple disciplines, perspectives and constituents in the field will be needed to be successful. This collaborative approach must be triggered so that quality of life for all can be improved in the near future. Acknowledgements The authors thank Gabrielle LeBlanc (Leblanc Bioscience Consulting, Berkeley, CA) for help in writing the manuscript. This review is based in part on an open scientific satellite 13
symposium titled “Aging: Therapeutics for a Healthy Future” held in conjunction with the 46th Annual Society for Neuroscience meeting in 2016, sponsored and organized by Charles River Laboratories. The meeting panelists included: Robert Hodgson (CNS Biology, Takeda, San Diego CA), Brian K. Kennedy (Yong Loo Lin School of Medicine, National University of Singapore, Buck Institute for Research on Ageing) , Eliezer Masliah (National Institute of Aging), Kimberly Scearce-Levie (Denali Therapeutics), Barbara Tate
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(Dementia Discovery Fund) and Steven P. Braithwaite (Alkahest Inc, San Carlos, CA).
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REFERENCES [1] Khan SS, Singer BD, Vaughan DE. Molecular and physiological manifestations and measurement of aging in humans. Aging Cell. 2017; Aug;16(4):624-633. doi: 10.1111/acel.12601 . [2] Soto-Gamez A, Demaria M. Therapeutic interventions for aging: The case of cellular senescence. Drug discovery today. 2017;22:786-795
of
[3] Erikson GA, Bodian DL, Rueda M, Molparia B, Scott ER, Scott-Van Zeeland AA, et al. Whole-genome sequencing of a healthy aging cohort. Cell. 2016;165:1002-1011
ro
[4] Niccoli T, Partridge L. Ageing as a risk factor for disease. Curr Biol. 2012;Sep 11;22(17):R741-52. doi: 10.1016/j.cub.2012.07.024.
[5] Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, et al. Geroscience:
-p
Linking aging to chronic disease. Cell. 2014;159:709-713 aging. Cell. 2013;153:1194-1217
re
[6] Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of [7] Pan H, Finkel T. Key proteins and pathways that regulate lifespan. The Journal of
lP
biological chemistry. 2017;292:6452-6460
[8] Gao AW, Uit de Bos J, Sterken MG, Kammenga JE, Smith RL, Houtkooper RH. Forward and reverse genetics approaches to uncover metabolic aging pathways in
ur na
Caenorhaditis elegans. Biochim Biophys Acta. 2017; pii:S0925-4439 (17) 30321-6. [9] Bitto A, Wang AM, Bennett CF, Kaeberlein M. Biochemical Genetics Pathways that Modulate Aging in Multiple Species. Cold Spring Harb Perspect Med. 2015; 5(11): pii:a025114
[10] Gladyshev VN. Aging: Progressive decline in fitness due to the rising deleteriome
Jo
adjusted by genetic, environmental, and stochastic processes. Aging cell. 2016;15:594-602 [11] Lucanic M, Plummer WT, Chen E, Harke J, Foulger AC, Onken B, et al. Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects. Nature communications. 2017;8:14256 [12] Wyss-Coray T. Ageing, neurodegeneration and brain rejuvenation. Nature. 2016;539:180-186 15
[13] Podtelezhnikov AA, Tanis KQ, Nebozhyn M, Ray WJ, Stone DJ, Loboda AP. Molecular insights into the pathogenesis of alzheimer's disease and its relationship to normal aging. PloS one. 2011;6:e29610 [14] Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 2011; 477
of
(7362):90-4 doi: 10.1038/nature10357 [15] Vaiserman A, Lushchak O. Implementation of longevity-promoting supplements
ro
and medications in public health practice: achievements, challenges and future
perspectives. J Transl Med. 2017; Jul 20;15(1):160. doi: 10.1186/s12967-017-12598.
-p
[16] Kõks S, Dogan S, Guvenc Tuna B, González-Navarro H, Potter P, Randenbroucke RE.
re
[17] Mouse models of ageing and their relevance to disease. Mechanisms of Ageing and Development 2016; 160: 41-53
lP
[18] Kalinkovich A, Livshits G. Sarcopenia- The search for emerging biomarkers. Ageing Res Rev 2015; 22:58-71 doi: 10.1016/j.arr.2015.05.001 [19] Ruan Q, D'Onofrio G, Sancarlo D, Greco A, Lozupone M, Seripa D, Panza F, Yu Z.
ur na
Emerging biomarkers and screening for cognitive frailty. 2017 Aging Clin Exp Res 29(6):1075-1086. doi: 10.1007/s40520-017-0741-8 [20] Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 2014 May 9;344(6184):630-4.
Jo
doi: 10.1126/science.1251141 [21] Helman A, Avrahami D, Klochendler A, Glaser B, Kaestner KH, Ben-Porath I, Dor Y. Effects of ageing and senescence on pancreatic β-cell function. Diabetes Obesity and Metabolism. 2016 Sep;18 Suppl 1:58-62. doi: 10.1111/dom.12719 [22] Smith LK, He Y, Park JS, Bieri G, Snethlage CE, Lin K, Gontier G, Wabl R, Plambeck KE, Udeochu J, Wheatley EG, Bouchard J, Eggel A, Narasimha R, Grant JL, Luo J, WyssCoray T, Villeda SA. β2-microglobulin is a systemic pro-aging factor that impairs 16
cognitive function and neurogenesis. Nature Medicine. 2015 Aug;21(8):932-7. doi: 10.1038/nm.3898 [23] Sallam N, Laher I. Exercise Modulates Oxidative Stress and Inflammation in Aging and Cardiovascular Diseases. Oxid Med Cell Longev.2016; 2016:7239639. doi: 10.1155/2016/7239639. [24] Ahmed AS, Sheng MH, Wasnik S, Baylink DJ, Lau KW. Effect of aging on stem cells. World J Exp Med. 2017 Feb 20;7(1):1-10. doi: 10.5493/wjem.v7.i1.1. hypertension. J Mol Cell Cardiol. 2015; Jun;83:112-21. doi:
ro
10.1016/j.yjmcc.2015.04.011.
of
[25] Harvey A, Montezano AC, Touyz RM. Vascular biology of ageing-Implications in
[26] Castellano JM, Mosher KI, Abbey RJ, McBride AA, James ML, Berdnik D, Shen JC, Zou B, Xie XS, Tingle M, Hinkson IV, Angst MS, Wyss-Coray T. Human umbilical cord
-p
plasma proteins revitalize hippocampal function in aged mice. Nature 2017 Apr 27;544(7651):488-492. doi: 10.1038/nature22067
re
[27] Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015; Dec;21(12):1424-
lP
35. doi: 10.1038/nm.4000.
[28] Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays
ur na
ageing-associated disorders. Nature. 2011; Nov 2;479(7372):232-6. doi: 10.1038/nature10600.
[29] Sala AJ, Bott LC, Morimoto RI. Shaping proteostasis at the cellular, tissue, and organismal level. The Journal of cell biology. 2017;216:1231-1241. [30] Dubinsky AN, Dastidar SG, Hsu CL, Zahra R, Djakovic SN, Duarte S, et al. Let-7
Jo
coordinately suppresses components of the amino acid sensing pathway to repress mtorc1 and induce autophagy. Cell metabolism. 2014;20:626-638 [31] Williams KW, Liu T, Kong X, Fukuda M, Deng Y, Berglund ED, et al. Xbp1s in pomc neurons connects er stress with energy balance and glucose homeostasis. Cell metabolism. 2014;20:471-482
17
[32] Tsai S, Sitzmann JM, Dastidar SG, Rodriguez AA, Vu SL, McDonald CE, et al. Muscle-specific 4e-bp1 signaling activation improves metabolic parameters during aging and obesity. The Journal of clinical investigation. 2015;125:2952-2964 [33] Kaushik S, Cuervo AM. Proteostasis and aging. Nature medicine. 2015;21:14061415 [34] McDaniel CF. Diabetes: A model of oxidative accelerated aging. Age (Omaha). 1999; Oct;22(4):145-8. doi: 10.1007/s11357-999-0016-1.
of
[35] Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox, JP, Schernthaner G, Mukherjee J, Currie CJ. Can people with type 2 diabetes live longer than those
ro
without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab. 2014; Nov;16(11):1165-73. doi: 10.1111/dom.12354.
-p
[36] Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, ScheibyeKnudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y,
re
Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;
lP
4:2192. doi: 10.1038/ncomms3192.
[37] Chen BH, Marioni RE, Colicino E, Peters MJ, Ward-Caviness CK, Tsai PC, et al. DNA methylation-based measures of biological age: Meta-analysis predicting time to
ur na
death. Aging. 2016;8:1844-1865
[38] Horvath S. DNA methylation age of human tissues and cell types. Genome biology. 2013;14:R115
[39] Wagner W. Epigenetic aging clocks in mice and men. Genome biology. 2017;18:107
Jo
[40] Stubbs TM, Bonder MJ, Stark AK, Krueger F, Team BIAC, von Meyenn F, et al. Multi-tissue DNA methylation age predictor in mouse. Genome biology. 2017;18:68 [41] Lucanic M, Plummer WT, Chen E, Harke J, Foulger AC, Onken B, et al. Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects. Nature communications. 2017;8:14256 [42] Nadon NL, Strong R, Miller RA, Nelson J, Javors M, Sharp ZD, et al. Design of aging intervention studies: The nia interventions testing program. Age. 2008;30:187-199 18
[43] Newman JC, Milman S, Hashmi SK, Austad SN, Kirkland JL, Halter JB, et al. Strategies and challenges in clinical trials targeting human aging. The journals of gerontology. Series A, Biological sciences and medical sciences. 2016;71:1424-1434 [44] Blagosklonny MV. From rapalogs to anti-aging formula. Oncotarget. 2017;8:35492-35507 [45] Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell metabolism. 2016;23:1060-106
of
[46] Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine.
ro
2018;36:18-28.
[47] Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat
-p
Med. 2016;22:78–83.
[48] Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, et al. Senolytic
re
therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model. Nat Neurosci. 2019;22(5):719-728.
lP
[49] Lamming DW, Ye L, Sabatini DM, Baur JA. Rapalogs and mTOR inhibitors as antiaging therapeutics. J Clin Invest. 2013;123(3):980-9. [50] Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene
ur na
leads to a syndrome resembling ageing. Nature. 1997;390(6655):45–51 [51] Sha SJ, Deutsch GK, Tian L, Richardson K, Coburn M et al. Safety, Tolerability, and Feasibility of Young Plasma Infusion in the Plasma for Alzheimer Symptom Amelioration Study: A Randomized Clinical Trial. JAMA Neurol. 2019;76(1):35-40. [52] Kheifets V, Braithwaite SP. Plasma-Based Strategies for Therapeutic Modulation
Jo
of Brain Aging. Neurotherapeutics. 2019;16(3):675-684. [53] Brooks RW, Robbins PD. Treating Age-Related Diseases with Somatic Stem Cells. Adv Exp Med Biol. 2018;1056:29-45. [54] Tamanini S, Comi GP, Corti S. In Vivo Transient and Partial Cell Reprogramming to Pluripotency as a Therapeutic Tool for Neurodegenerative Diseases. Mol Neurobiol. 2018;55(8):6850-6862.
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[55] Shay JW, Wright WE. Telomeres and telomerase: three decades of progress. Nat Rev Genet. 2019;20(5):299-309. [56] Michan S. Calorie restriction and NAD⁺/sirtuin counteract the hallmarks of aging. Front Biosci 2014;19:1300-19. [57] Anton S, Leeuwenburgh C. Fasting or caloric restriction for healthy aging. Exp Gerontol. 2013;48(10):1003-5. [58] Kivipelto M, Mangialasche F, Ngandu T. Lifestyle interventions to prevent
of
cognitive impairment, dementia and Alzheimer disease. Nat Rev Neurol. 2018;14(11):653-666.
Jo
ur na
lP
re
-p
ro
[59] Kramer AF, Erickson KI, Colcombe SJ. Exercise, cognition, and the aging brain. J Appl Physiol 2006;101:1237-1242.
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Figure 1: The brain and peripheral organs share common biological mechanisms of aging. The well described pillars of aging6 are evident systemically, linking the neurological and behavioral consequences of aging and peripheral organs whose function also declines with age. A strong hope for therapeutics of aging is that a cross-therapeutic area benefit will be achieved
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Table 1: Key therapeutic strategies for aging biology Therapeutic Candidates
48 49 19, 21, 50, 51 52 53 54 55
55,56, 57 57, 58
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Multiple regimens Multiple regimens
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Non-Pharmacological Caloric Restriction Exercise
44 45, 46, 47
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Metformin (Biguanides) Fisetin, Bcl2 inhibitors, Dasatinib, Quecertin Proteostasis/autophagy Rapamycin, Rapalogs Nutrient Sensing Klotho Intercellular signaling Plasma, Plasma Fractions, GDF11 Stem cell exhaustion Mesenchymal stem cells Epigenetic Yamanaka factors reprogramming Telomere shortening Telomerase Genomic Instability NAD+
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Pharmacological Metabolic function Cellular Senescence
References
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Process