Bottlenecks
of Aging

Even if a biotech company discovered an effective lifespan-extending drug today, it’s unlikely they could develop it economically under the current regulatory framework. Since death is a rare event in people without serious disease, it could take decades to conduct drug trials capable of demonstrating a statistically significant benefit on mortality. Such trials would necessarily be large and expensive, with no guarantee of a return on investment: depending on the age of the participants at enrollment, the drug’s patent may even expire before the end of the trial.

Hard functional endpoints and surrogate measures of aging could solve this bottleneck. Regulators typically want to see a drug demonstrate a benefit on how a patient “feels, functions, or survives” prior to approval. One approach is to develop surrogate endpoints. While not direct measures of function, they are intended to offer a quick method of predicting decline – like how high blood pressure predicts cardiovascular disease. Another, less common approach is to create a battery of physical and cognitive tests that directly measure function. Developing and validating new endpoints of aging, such as molecular biomarker clocks and frailty indexes, will be a critical step towards building a viable path for biotech companies to develop aging drugs in years, rather than decades.

Active Projects

Recommendations for Proposals and Funders

1. Statistical paper(s) to quantify the difficulty of a lifespan-extending study based on trial size and theoretical drug efficacy. Simulations of trials with survival as a primary endpoint under various parameters of drug efficacy (mortality risk reduction), population under study, and trial size would help the field and policymakers evaluate trade-offs in study design and population.

2. Clinical trials that bridge aging and other diseases to reduce accelerated aging phenotypes. For example, childhood cancer survivors age more rapidly.

3. Expanding the TAME trial, one of the first proposed human clinical trials for an aging drug, to include exercise and combinatorial drug interventions.

Past the age of thirty, our brains begin to shrink at a rate of around 5% a decade. Neurons, other cells, and synapses are either lost or become dysfunctional. Neurotoxic protein plaques, such as amyloid-beta and neurofibrillary tangles, accumulate in and between neurons. Processing speed, memory, and reasoning capabilities steadily decline.

Cells in aged brains show many of the same impairments common to other aged tissues: mitochondrial dysfunction, calcium dysregulation, defective proteostasis, and inflammation among them. While a distinction is often made between ‘healthy’ brain aging and age-related neurodegenerative diseases, the boundary between normal and abnormal neurodegeneration is blurred: it has been suggested that if we lived long enough, many of us would eventually develop dementia.

Most current brain aging research focuses on accelerated late-stage forms of brain aging like Alzheimer’s and Parkinson’s. However, billions of dollars spent on clinical trials for these conditions have mostly failed to deliver treatments that meaningfully slow cognitive decline. By focusing on specific, severe manifestations of a broader pattern of age-related decline we have likely missed insights that would allow us to remediate the root cause: aging itself. Our white paper and workshop — led by internal Amaranth lead Rohan Krajeski — outlines a way to understand and target brain aging directly.

Research We’ve Funded

1. Comprehensive multi-modal analysis of aging and and aging reversal (Harvard, MIT, Scripps)

2. The pathogenic role of disrupted glutathione homeostasis in Alzheimer’s Disease (Augusta)

3. In vivo CRISPR screens to identify neuronal genetic vulnerabilities and protective genes in aging and related neurodegeneration (ETH Zurich)

4. Cellular rejuvenation landscape in aging neurons (MIT)

5. Novel ultrasound technology (Convergent Research)

6. Aging brain proteomics (Yale)

Recommendations for Proposals and Funders

For a full scientific breakdown of moonshots in this field, see this white paper.

1. Generating pure and highly specific populations of hard-to-make brain cell types and tissues (e.g. microglia, astrocytes, specific neuronal subtypes).

2. Characterizing survival, integration, and function of exogenously transplanted cells in vivo.

3. Fund overlooked model systems for nerve injuries such as whole-eye transplantation and full transection of nerves, such as in spinal cord injury.

4. Studying and translating special regenerative capabilities in central nervous systems of exotic species to mammals. This includes replication studies of past papers and the discovery of new mechanisms. Remarkably, some of these animals can regenerate parts of their brain (e.g. songbirds, killifish, axolotls, lamprey, planaria).

5. Increasing therapeutic tools to treat and remodel the extracellular matrix in the brain [see Priority 8]. For example, ex-vivo studies of transplanted young neurons onto stiff extracellular matrices result in the rapid aging of transplanted cells.

6. Study possible cerebrospinal fluid biomarkers associated with brain and spinal cord aging. Outside of non-invasive imaging techniques, blood-based biomarkers are often used, however some proteins may present at lower levels in the blood than in the CSF, which may make it tricky to monitor gradual changes in cognitive health. 

7. Increase access to non-human primate brain samples, especially for aged brains [see Priority 7]. These can be valuable resources for studying overall brain aging.

Moonshot approaches like controlled reprogramming may fail or result in very limited gains. To fully map out the biology of aging, we may need several decades. Yet even if aging cannot be holistically understood in the near term, aging body parts can be replaced — as shown by the replacement of cells, organs, blood, and tissues since the 1950’s.

The organs and tissues of the body accumulate thousands of types of molecular damage as they age: cells fill with lipofuscin, arteries clog with plaque, and healthy tissue becomes fibrotic and stiff. Such extensive damage presents a challenge for biomedicine. Modern medicines are precise molecular scalpels: each drug is designed to hit one, or a small number, of molecular targets. Today’s drugs are often ill-suited to repair the widespread, complex patterns of damage seen in aging.

Personalized cocktails made up of tens or hundreds of individual drug molecules are one potential solution to this problem. But there may be a better way: directly replacing damaged organs and tissues with healthy ones. Transplantation of organs, tissues (e.g. cartilage), and cells from human donors is a time-tested method. However, there are also many risks associated with transplants. Immunosuppressants required to prevent rejection of foreign tissues are toxic, and lead to deaths from opportunistic infections and cancer. Waiting lists for donors are years long, and many would-be recipients die waiting. We need more organs and tissues, and better ways of keeping them healthy post-transplant.

We could benefit from a shift in perspective towards seeing organ, tissue, and cell replacement as a new category of therapeutics: an extension of the ongoing trend towards larger and more sophisticated medicines. (Think small molecules in the early 1900s, biologics in the 80s, and cell and gene therapy in the 2010s). We want to support bold scientific ideas with the potential to realize this vision: scalable organ manufacturing, xenotransplantation, replacement tissues for intricate structures like the brain, and tissues or organs from patient-derived cells. Revitalizing the stagnant science of transplantation with new congresses, and offering support for promising scientists, will be critical steps towards accessible, safe, scaleable, and standardized replacement therapies.

Research We’ve Funded

1. Replacing an old blood and immune system with a young one (Stanford)

Recommendations for Proposals and Funders

1. Generating transplantation-ready organs inside animals. Current research shows that it is possible to generate non-host organs inside a chimeric host. This could provide a potential pathway for the generation of organs with minimal immune suppression required post-transplantation.

2. More shots on goal for xenotransplantation and cryopreservation of organs.

3. Alternative methods to immunosuppression such as antibody treatment and growing patient-specific hematopoietic stem cells for bone marrow transplantation (e.g. via synthetic embryos, stem cell differentiation, bioprinting).

4. Validating brain tissue and cell replacement as the next phase of therapies from small molecules to proteins and cells [see Priority 2].

5. Whole-eye transplantation as a clinical replacement approach within the Overton window to study axon regeneration from transections [see Priority 2].

The longevity field is experiencing exponential growth, with a 70-fold increase in funding since the last decade, and growing interest from established pharmaceutical companies. Yet the pipeline to funnel talented people into aging research remains underdeveloped. People with the potential to do impactful work in aging are often directed elsewhere. Consequently, the talent pool available to labs and longevity biotech companies is small relative to the need.

Bringing new attention, advocacy, and resources to neglected fields can be a powerful driver of progress. Consider the Cystic Fibrosis Foundation (CFF). In 1955, when the foundation was established, the life expectancy of a child born with cystic fibrosis was about 2 years. A child born with the same condition today can expect to live nearly as long as his or her peers without it. This achievement is to a large extent attributable to the support the CFF gave to researchers and biotech companies in their search for new treatments. What the CFF did for cystic fibrosis, we want to see done for aging. Increasing the recruitment and retention of new talent into aging research is a prerequisite to executing on all promising research directions. To achieve this, graduate student pipeline issues need to be resolved; new PIs need to be motivated to take on innovative age-related research projects; and the pool of operators for new longevity biotech companies needs to be expanded.

Active Projects

Recommendations for Proposals and Funders

1. Increase the number of ARPA-H proposals for longevity. The overall number of longevity proposals submitted for review could be increased, for example, if a full-time grant writer were funded to serve all labs interested in studying aging.

2. Recruit talent from outside of the United States into the longevity space. The Norn Group has created such an initiative, and they are actively looking for collaborators, applicants, and donors.

Since the mid 1800s, advances in nutrition and medicine have increased life expectancy at a rate of about 3 months every year. Yet despite this progress and decades of work on longevity, maximum lifespan has proven stubbornly difficult to shift – even though there’s no good evidence to suggest a fixed upper limit exists. With the current pace of progress in longevity research, countless patients will die from age-related illnesses in the coming decade – in particular older adults and those who are terminally ill. To protect our most vulnerable populations and offer them the chance to catch up to advancements in medicine, we may need a plan B: biopreservation.

Biopreservation may seem like the stuff of science fiction. Yet biopreservation is not just full-body cryonics and stasis chambers for interstellar voyages. Work has already started on tools and techniques with near-term applications: DARPA funded research into wound stasis technologies for injured soldiers, therapeutic hypothermia to improve outcomes post-resuscitation, warm-perfusion methods to keep donor organs viable outside the body. There is even an NSF-funded center for the preservation of biological systems. These are important stepping stones. Eventually, cryogenics, and other preservation technologies, could allow people and organs to be preserved until medical science has caught up, allowing them to live longer than they ever could in their original time period of birth – especially for those with as yet untreatable, terminal diseases.

Today, biopreservation technologies remain underfunded, understudied, and understaffed. The few existing for-profit efforts have not yet solved the scientific problem of freeze-thaw without ice crystal damage; while nonprofits have so far proven unable to catalyze needed advancements in this area of science. The field as a whole continues to mostly exist outside the purview of traditional science, with a few nascent government, academic, and venture capital funds devoted to cryonics, vitrification, hibernation, perfusion, or torpor. To realize this vision, the field will need significant investment to develop talent, build credibility, and spin up new collaborations between researchers and institutions.

Research We’ve Funded

1. Pilot study on helium-assisted vitrification of porcine kidneys (Independent)

Recommendations for Proposals and Funders

1. Increase funding for development of non-model organisms that have complex biopreservation abilities (e.g. ground squirrels).

2. Large-scale screens for novel cryoprotective agents and proteins.

3. Increasing the number of assays that can be conducted at low (-80°C) temperatures to differentiate between damage from freezing and damage from rewarming.

4. Method validation of currently existing assays.

5. More shots on goal for whole-organism cryopreservation of small animals.

6. Database that lists all cryoprotectants and their effects on different cell types along with multimodal data (scRNA-seq, microscopy images).

7. Fundable opportunities for scientists highlighted in this paper, deep freezing entire organs and bringing it back to life.

Drugs such as metformin and rapamycin appear to only modestly increase the human health-span and lifespan. We will need new drugs with additional, complementary mechanisms of action if we hope to meaningfully extend our lives. By identifying new ways of intervening in the aging process (e.g., new drug targets), we can enable the biotech industry to bring its considerable target-based discovery machinery to bear on finding the next generation of therapies which intervene holistically in human aging.

The aging field has only built consensus around a small number of targets, most of which were discovered from work in yeast, worm, or rodent model organisms in relatively low throughput experiments. More recent high-throughput screens have not found many robust targets and have been time-consuming and expensive. We hope to build on and surpass previous target-finding efforts by substantially expanding the search space for new drug targets which intervene in the aging process.  New high-throughput screening methods, large-scale drug screens in mice, and sequencing centenarians to identify rare genomic variants associated with long life are promising target-finding initiatives which could ensure the drug development pipeline for aging remains full.

Active Projects

Recommendations for Proposals and Funders

1. Large-scale aging screens in rodent models to test a large number of genetic, protein, or small molecule interventions to extend lifespan. This development would accelerate our understanding of mammalian aging and our knowledge of promising interventions.

2. Novel target discovery in different species with exceptional life spans or superpowers (like the bowhead whale’s ability to live for centuries in good health).

3. Being able to capitalize on the large number of ongoing trials for the diseases of aging—as opposed to focusing on rare healthspan trials—is a critical factor in the speed of progress in the aging field. To accelerate the discovery of appropriate drug targets, longevity biomarkers can be validated, for example, by pairing with clinical trials of other diseases that present accelerated aging phenotypes such as childhood cancer, Alzheimer’s, diabetes, and more [see Priority 1].

Animal or tissue models are required to test potential aging drugs and interventions. However, common models of age-associated diseases like the tg2576 mouse model of Alzheimer’s, and other physiological aging models only recapitulate a fraction of these conditions’ complex biology. Oversimplified disease models fail to reliably predict outcomes in the real disease, and contribute to high clinical trial failure rates of drugs for diseases like Alzheimer’s. Though it would often be preferable to use naturally aged animal models to study aging and associated diseases, these models are resource- and time-intensive to produce or procure, and hence, their availability is limited.

The combination of low availability; limited allocation per investigator; lack of genetically diverse lines; and high costs of aged animal models creates a significant bottleneck in the longevity field. This, in turn, limits the rate at which potential drugs and interventions can be tested and leads researchers and biotech companies to turn on simpler, unnatural, and unreliable models. Investing in a new Contract Research Organizations (CROs) to produce genetically diverse aged animals and exotic animal models, while expanding monkey facilities and lobbying for continued animal research would expand the availability of aged animal models for research.

Recommendations for Proposals and Funders

1. Supporting partnerships with biobanks like the UK Biobank to collect tissue and samples relevant to aging researchers to validate biomarkers around the world.

2. Aged animal CRO. A contract research organization to produce genetically diverse aged research animals at an affordable cost is necessary for researchers (e.g. rodents, monkeys).

3. Increasing funding for the development of non-model organisms in aging research (e.g. killifish, songbirds).

4. Biobanking long-lived organisms for researchers to access such as aged tissues from naturally-dying or legally-fished giant tortoises, red sea urchins, immortal jellyfish, olms, naked mole rats, ocean clams, bowhead whales, greenlandic sharks, lobsters, and tuataras.

5. Establishing partnerships with non-human primate facilities on behalf of aging scientists to quickly onboard new researchers in search of certain tissues and animals.

The composition of aged tissues is different from that of young tissues. To date, we have only partly characterized the damage that occurs with aging. Known age-related changes include accumulation of damaged, nonfunctional biomolecules in the extracellular and intracellular spaces (e.g. amyloid plaques, lipofuscin), and chemical alterations to long-lived, functional biomolecules (e.g. stiffening and crosslinking of collagens and histones; damage to DNA). These microscopic forms of damage likely lead to the macroscopic changes and functional impairments seen in aged tissues.  

To fix age-associated damage, we may need to first understand it. Yet even among known forms of damage, a detailed molecular understanding is often lacking. One promising direction is to fund research to better characterize established types of age-related damage and discover new forms of damage. Another is to kickstart initiatives with the goal of finding ways to therapeutically intervene to remove and repair age-related damage.

Research We’ve Funded

1. Direct exploration of the effects of protein glycation in age-related disease (Tufts)

2. Elucidating the full structure of glucuronidine/LW1 (Case Western)

Recommendations for Proposals and Funders

1. Discovering new types of overlooked damage. Examples of potential targets include new protein aggregates, matrix crosslinks, and lipo-oxidation products.

2. Developing new assays for known types of damage.

3. Testing the hypothesis that intracellular changes (e.g. ER stress) can lead to tissue and organism-wide improvements.

4. Increasing therapeutic tools to treat and remodel the extracellular matrix in tissues outside the brain. The extracellular matrix is proposed to be involved in many hallmarks of aging, as well as with the progression of cancer.

5. Generating standardized lipofuscin, which has been linked to cellular dysfunction and death, cellular senescence, and DNA, lipid, and protein damage.

We don’t yet know how to prevent our bodies from aging. However, a subset of our cells have effectively already solved the problem of damage accumulation. Germ cells naturally reset damage and rejuvenate through the process of fertilization and development. Egg cells, for instance, can clear out toxic protein aggregates before they mature, preventing them from being passed on. This regenerative capability means germline cells have persisted for billions of years without succumbing to the damage that normally shuts down old cells. As a result, old germ cells can spawn young animals and keep biological lineages going indefinitely.

Deciphering the mechanisms of germ cell rejuvenation and how to apply them throughout the body is a promising path. Yet germline immortality remains overlooked. To unlock novel rejuvenation techniques, we must nurture and expand the scientific subfields which possess the potential to translate rejuvenation into humans, including germline rejuvenation and rejuvenation screening approaches.

Research We’ve Funded

1. Proteome rejuvenation in vertebrate oocytes - germline reset in Xenopus frogs (Harvard)

Recommendations for Proposals and Funders

1. Field building with an annual seminar to connect researchers in a small nascent field, or workshop to roadmap biggest unanswered questions regarding germline rejuvenation. Some unanswered questions include the below:

   1. Understanding current mechanisms of germline rejuvenation (e.g. by gamete formation).

   2. Rejuvenation vs. clonal selection (e.g. resistance to decline or active rejuvenation).

   3. Consequences of failure to rejuvenate or clonally select (e.g. unviable oocytes, germline aging, fertility).

2. Funding grants for basic research to study the mechanisms of germline rejuvenation.

3. Screening for transcription-factor based rejuvenation, chemical reprogramming, and protein reprogramming in germline model systems.

Historically, biology has advanced at the speed of its tools. Tools and techniques like restriction enzymes, confocal microscopy, electron microscopy, optogenetics, and CRISPR have given us a deep understanding of cellular processes, and enabled us to intervene therapeutically at the molecular scale. Increasingly, the biologist's toolkit is not just molecular, but computational too. Bioinformatics and in silico screening are by now entrenched in drug discovery. Domain specific artificial intelligence models like AlphaFold and protein language models are poised to transform how we model, understand, and drug biological systems. However, tools alone are insufficient for breakthroughs. In order to drive advances, funding and insights are needed to motivate scientists to point their promising new tools towards specific research questions.

As a rule, breakthroughs in tool development lead to breakthroughs in fundamental science. We expect this to be particularly true of geroscience. Before we are ready to untangle the complex and multifaceted web of changes that occur in aging organisms, we need better tools. We need molecular tools to more finely perturb and probe aging systems, and we need computational tools to process, model, and make sense of the information we gather. 

We want to ensure that scientists are willing and able to apply new tools to further our understanding of aging holistically - beyond what has been learned from the reductionist exploration of the 'hallmarks of aging' in isolation. To achieve this, scientists must first be inspired to apply their tools to relevant research questions. Second, they must have the funding to support them through solving the kinks that occur with any new set of tools.

Learning More

• Untangling Aging Using Dynamic, Organism-Level Phenotypic Networks 

• Hallmarks of Aging: An Expanding Universe

• A complex systems approach to aging biology

• scDiffCom: a tool for differential analysis of cell–cell interactions provides a mouse atlas of aging changes in intercellular communication

Recommendations for Proposals and Funders

Open call.

Narratives are powerful drivers of social change. The idea that progress is possible, even desirable, was once controversial and not widely accepted. Narratives shaped during the Enlightenment and the Industrial Revolution embedded the concept of progress in society, now taken for granted. The same narrative shift is needed for life extension.

Humanity’s quest for eternal life has attracted criticism for millenia, ever since the first recorded work of literature: The Epic of Gilgamesh. Today, life-extending technologies are still widely associated with overindulgence and greed. There is a growing appetite for content related to human longevity — yet communication with the public on the socio-economic and philosophical aspects of this new science is lacking.

We believe new stories are needed to legitimize aging research, cryopreservation, and other life-extending technologies as credible and socially desirable pursuits. To achieve this, speakers and writers from the aging field will need support to break into separate, more established fields, beyond the aging community. 

New stories — told through events, movies, books, documentaries, artwork, opinion pieces, and university courses — are necessary to challenge the centuries-old tales which confer negative associations to life extension.

Active Projects

Recommendations for Proposals and Funders

1. Increase the number of writings on the philosophy and ethics of aging addressing the mainstream objections to aging research.

2. Organize art and education exhibits in museums, public spaces, and universities. The Museum of Science in Boston has expressed interest in a longevity exhibit, as have various artists in putting together art pieces on the themes of life, aging, and death.

3. Develop introductory material with longbio leaders (e.g. short course, lab list, and data repository of foundational research) that can be used to recruit young talent into the aging field and educate them about the history of aging biology.

4. Supporting writing contests like the Ideas Matter writing challenge to explore positive visions of a biological future with longevity research.

It is often said that what gets measured gets managed. Economic datasets are known to have fueled investment into different industries, in some cases leading to the bottom-up creation of entirely new sectors. The aging field lacks such comprehensive studies, in no small part because the socio-economic effects of aging (including age-related entitlement programs like Medicare) are seen as unmodifiable. 

New efforts are needed to arm philanthropists, investors, and policymakers with data on the short- and long-term effects of their capital allocation in science, where the goal is to lessen the burdens of disease and social care.

We will support the development of economic models, explained in reader-friendly language and published alongside respected economists in high-visibility, general audience media. Our project on this topic is led by Amaranth internal lead Raiany Romanni.

This report will contain interactive graphs and maps with exclusive data on different countries’ economic health relative to their demographic profile, highlighting the rationale for the investment of government, philanthropic, and private funds into research and trials aimed at extending health. The data findings will be disseminated across educational videos, opinion pieces, and one long-form report.

Active Projects