Research Portfolio

We are excited to announce both Research Portfolio, a new way to fund research, and the Amaranth Prize, a $250k prize for longevity powered by Research Portfolio. The prize is supported by the Amaranth Foundation, an organization who has committed immense and crucial resources to longevity research.

To learn more about Research Portfolio, visit our FAQ or our Manifesto for details. This piece explains why we built a new funding layer for research, its design principles, and how it works. Contact support@researchportfolio.co if you have questions, comments, or suggested improvements.

TL;DR

We built a new way to fund research. It a) retrospectively funds b) the paper itself (rather than the lab) and c) additionally allocates a portion of the funding to a paper’s most important parent papers.

We call this Research Portfolio, and it is in spirit similar to the Retroactive Public Good Funding work proposed by Vitalik Buterin and Optimism. It is built on the Ethereum blockchain, which is vital because it enables philanthropists to trivially fund any distribution of recipients on the blockchain, even to authors who don’t have known Ethereum wallets.

Read on to learn about how research funding works today, why we built this, and details on our design choices. The bottom half enumerates the winners of the Amaranth Prize. Before we dive in though, let’s make one thing clear:

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There is no global Research Portfolio token. The organization behind Research Portfolio doesn’t make any money from the system and only receives tokens earmarked for influential papers. All tokens associated with Research Portfolio are minted by (or for) the authors to represent their papers.

Research, Startups, and the Value Chain

Here’s a very brief profile of Research’s profile:

There’s a tremendous amount of uncertainty as to what will be worth publishing.

There’s even more uncertainty as to what will rewrite textbooks, change the field, and be notable decades from now. Sometimes the Nobel winning science isn’t even accepted for publishing.

Occasionally, research does change what society thought was possible.

Along the way, scientists have to fund their work, but funding is:

Exponentially biased to chase big discoveries and already hot areas, leading to mostly incremental research on top of the already found vein of new knowledge instead of to left field ideas that could be the source of the next big discovery.
Most often sourced from groups that are surface knowledgeable (philanthropists) or have built-in conservatism towards the old ways;
Limited.

This looks familiar. Let’s substitute startups for research:

There’s a tremendous amount of uncertainty as to which (team, business) pairings will work well.

There’s even more uncertainty as to what will be a huge outcome, change the course of humanity, and still be a big business decades from now.

Occasionally startups do change what society thought was possible.

Along the way, startups have to fund their work, but funding is:

Exponentially biased to chase huge business potential and already hot areas, leading to mostly copycat businesses (“Uber for X”).
Most often sourced from groups that are surface knowledgeable (venture capitalists) or have built-in conservatism towards the old ways (”who wants to stay in someone’s spare room???”).
Limited … but exponentially less so than in research.

The biggest differences between research and startups are that startups are closer to where enterprise value is made and that startups have an exit at the end. In a Wardley mapping sense, research is the far left of the business evolution stage and startups are most often close to the custom/product divide. An investor in a startup is taking a bet that the payoff for committing capital will be high over a relatively short amount of time. On the other hand, a philanthropist may never even see the fruit of their input. They are doing it either because they love the cause or because they want more status or a host of other, less prominent reasons.

Humanity moves forward together: Startups learn from Research; Industry learns from Startups; Then Research learns from Industry. However, Startups and Industry deal in the same currency (money) while Research runs off of status. This is a consequence of the limited amounts of capital and positions in Research vs that of Startups and Industry.

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Research Portfolio is an effort to change that reliance on status and unite these different modes all under one banner. It is an effort to gift the Research community with a direct link to the funding that flows from end users through the value chain all the way back to research itself.

Fund Retrospectively.

From the perspective of the funder, most research funding models are prospective. This means that they issue a call for projects to fund in a certain domain, examine those projects for merit, and then decide what to fund. Our stance is that this status quo should change and that much more funding should be retrospective.

One reason is that funders have to guess what will be worth doing rather than the researchers in the trenches doing the work. Playing on Vitalik’s words, it’s easier to agree on what was impactful work than to predict what will be impactful. The latter is the job of a researcher and funders do a poor job of this.

Another reason is because prospective funding goes mostly to people based on reputation rather than on quality of [recent] work. This is known as the Matthew Effect.

And we absolutely know it should change because the research community has built paths around this approach. Most of the time, a prospective grant is responded to with work that’s already been done, but just not yet published. The grant funding is then used to work on the next pursuit. This is effectively retrospective funding where the funder is just kept in the dark.

From the perspective of researchers, the system is already retrospective but with extra work to maintain the illusion.

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Research Portfolio is retrospective. We are rewarding fantastic work after it’s been done. That is the only time when you know for sure that it’s impactful. It’s also the only time when you can slice and dice the funding precisely and with confidence fund tranches like “The best work in Algebraic Topology over the last 5 years performed by people of color in the American Southwest”.

How do researchers get started if we use retrospective funding?

One concern we often hear about retrospective funding is how do people get started in a system dominated by retrospective funding. While we aren’t positing the world where there’s no prospective funding, let’s examine this question.

Today, the most common route into a career in research is to apply to a lab and join as a PhD student, then spend an average of 3-5 years doing research under a professor from whose grant rewards the student is funded. After the student graduates, they either go do a postdoc, get a professorship immediately, or join a company. In all three scenarios, it’s because someone else - respectively another professor, a university, or a hiring manager - thought that the student did strong work and should join their team. That funding is retrospective. And from there on out, all of their funding is retrospective.

For example, once a professor starts at a university, the university gives them starter funds. This came because the university valued their prior work enough to hire them as a new professor. They then get grants based on more work that their lab does. Those grants might be declared as prospective, but as we detailed above, they are in practice retrospective.

In other words, retrospective funding doesn’t impact how researchers get started because the dominant amount of starter funding comes from universities and thereafter it actually already is retrospective in practice.

Fund Papers Directly.

When funders give money to research, they most often give to the Lab. In universities, this is represented by a specific principal investigator (PI), and a bunch of that money goes to the university itself. In companies, this is a specific team.

This funding is two levels too high.

The level below the Lab is the researcher themselves. The level below the researcher is the paper.

The unit of funding should be the paper and not the researcher or the lab.

A major benefit of this is that the funder can better harness their influence. A prize set up to reward recipients every two years for “Protein Aging” does not actually complete its stated purpose if it’s given generically to a lab because that funding could go to anything. The consequence is that funders apply stipulations on how the prize money can be spent.

This is counterproductive to how research works. Because outcomes are so hard to predict, researchers should have carte blanche to do with the money what they wish. The philanthropic influence on outcomes should come from the fact that the prize exists and runs consistently. That is sufficient because then that field will mature with the researchers who are most passionate and interested in that line of inquiry.

On the other hand, by giving to the works themselves, it frees up the researchers to follow their nose and be appropriately rewarded for doing so while simultaneously freeing up funders to focus their capital on the impact they care most about. When someone wants to fund a specific lab, that’s funding all the papers in that lab. When they want to fund a person, that’s funding all of their papers. This also serves to fund the people or that lab works with, which is correct. No one does it alone and funding should recognize that.

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Research Portfolio funds the papers directly. Authors get a share of that funding based on whether they were a first author, middle author, or principal investigator. They can claim this easily through our interface.

Fund the Tree.

Research depends on the shoulder of giants. There is hardly any paper that was made in a vacuum, but rather borrows from a select set of prior work. We think that this work can be distilled to at least one and at most five papers, and those parent papers should receive a chunk of funding that goes to a given paper. Moreover, this is recursive.

An important reason why is that there are very important works that are not flashy but just as necessary for the flashy work. An example are the methods and hardware papers in biology. They get many citations because they are crucial to downstream papers, but no one in the public eye or philanthropic circles are dying to talk about or fund a new tool. That is true even if the tool leads to breakthroughs like CRISPR.

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Research Portfolio requires that authors tell us a small number of papers upon which their work depends (min one, max five), as well as the percentage weight amongst those parent papers. Then twenty percent of any funds they receive are given proportionally to those parent papers. This happens recursively.

Research Portfolio

The above builds up to what we’ve created - Research Portfolio. Our motivations were to create 1) a platform for granting retrospective rewards 2) to the papers themselves that 3) gave proper due to the research tree and 4) was easy to extend to other use cases.

Further, these motivations suggested building this on blockchain (Ethereum) and smart contracts for three reasons:

It’s trivial to very quickly distribute a prize (or many), a challenge, or really any distribution of funds on the blockchain, even to non-existent entities, and it’s quite difficult to do so in real life. Rewarding the twenty authors on a paper would usually require finding bank information for all of them and then sending twenty bank wires. Instead, we can set up embedded wallets (using Privy) gated by their email sign-in, distribute the right allocation to those wallets, and then notify them by email.

We can actually enforce giving proper due to the research tree and those who came before you. People in the research world are some of the nicest folks you’ll come across - at their core they all just want to push forward our global understanding of the world. However, it is especially competitive when it comes to jobs and funding, because they are in limited supply. In private, everyone knows what papers are amazing, but in public and in funding submissions they will justifiably bias to tooting their own horn. In our system, everything is public by default because it’s on the blockchain, and so everyone plays by the rules or they will get called out.

Finally, it’s incredibly extensible. The fourteen papers that we minted for the Amaranth Prize each have their own token that can be used for whatever other purpose the authors want to consider. But as part of the prize there’s also funding that’s been distributed to their parent and grandparent papers as well, which means that we expect at the end of this to have 100+ papers minted from one domain. These can be experimented with in the name of advancing research.

How does Research Portfolio work?

Our system is designed to make it easy to mint paper-specific tokens on Ethereum Mainnet representing research. On our website, there are faculties for minting anyone’s paper as a token, for viewing already minted papers, for seeing your balance of tokens, and for claiming tokens that you deserve. In the spirit of other public goods on the blockchain, all of this is also available by directly manipulating the contracts on Etherscan or similar.

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Reminder: There is NO global Research Portfolio token. There are only paper-specific tokens either minted by an author or condoned by them.

An experiment in improving research processes Every minted paper is a fungible token, known as an ERC20. This allows for anyone to experiment with other needed improvements to research. Examples include better processes for replication, for challenging results, and for supporting underrepresented communities. It also allows for easy interoperability with the immense scaffolding and capabilities already built in Ethereum.

Respecting prior work When an author mints one of their papers as a token on our website, www.researchportfolio.co, they receive 80% of the tokens. The other 20% are distributed to the papers (min one, max five) that most influenced their work. The author specifies these influential papers and their corresponding influence percentages when minting. For influential works that aren’t yet minted, we hold their rewards in our Safe and promise to deliver upon minting. For those works that are already minted and verified, we do a real-time search for who owns those tokens, aggregate them by allocation, then automatically distribute the new tokens to those owners in accordance with their allocation. This is done via a Merkle Distribution, originally made famous by Uniswap’s airdrop as a low-cost way to distribute and claim funds.

Recursive respect for prior work What we described above works recursively. If I mint a paper paying heed to paper A with the full 20% allocation, and then another paper mints one granting my paper 10% of its tokens (50% of the 20% allocation), then the holders of A receive a proportional allocation of 2% of that paper. In this way, papers that are very influential but not necessarily that flashy get their due. Methods and equipment papers exemplify this well.

How does verification work? Anyone can mint any paper. We can’t and shouldn’t stop people from doing this. For one thing, it means that external services can help mint papers without the authors having to do it themselves. Instead, we act as the vigilant service in charge of ensuring that verification is bestowed only on papers with proper provenance. In other words, we arbitrate whether a token has been certified by a first author or principal investigator as a representative paper. This is trivial on open journals like Arxiv where the token hash can be pasted into the comments field and only the submitting author can make such changes. We look forward to the day when other journals are as easy to add supplementary information. In the meantime, we rely on the fact that DKIM signatures in email are in broad use today, and every reputable paper has an accompanying contact email. When we need to make such provenance clear, we’ll do so with services like ZKEmail.

Fixed paper allocation At the time of minting, 20% of the tokens go to prior work and the remaining 80% go to the authors. That latter 80% is arranged so that first authors split 70%, middle authors 10%, and principle investigators 20%. If a middle author was to get more than a PI or a first author, then the allocation is adjusted so that they get the same amount. This arrangement was decided after talking with researchers from a range of different fields. By making it uniform, the decision is on us instead of the minting author. The one field where we heard pushback on this arrangement was Economics where there were some calls for strict equality.

ERC1155, ERC20, and Placeholders

We built a version of Research Portfolio where the tokens were both ERC1155s and ERC20s. The original motivation for this was to get the benefits of interoperability with the immense infrastructure built for the fungible parts of Ethereum, as well as discoverability on platforms like OpenSea. This required a little bit of finessing the contracts to work together, but it worked well! One caveat was that MetaMask would no longer recognize the contract as an ERC20 by default, but insisted on it being an NFT and going in its NFT section; users would have to manually click our “Add Token” button to change this.

To be clear, we don’t mean that it served as both in every situation. That would be hard to, for example, exchange fractional ownership of the fungible part and still preserve the right amount of the non-fungible part. Instead, there was a fungible mint and a non-fungible mintBatch. The former created ERC20 tokens used for trading on exchanges. The latter created ERC1155 tokens called “Placeholders” for both authors and reference papers. For each author, a Placeholder was minted so that their share, as well as recursive shares of child papers, could accumulate at that address. These were all given to the minter and they would distribute the Placeholders to the respective authors. We had a similar approach for minting reference paper Placeholders for those papers that weren’t yet minted or verified.

An important point to note was that it was a step in the direction of removing the Research Portfolio organization as a trusted third party. This isn’t just crypto ideology; it’s actually ideal from the perspective of having a public good that can stand on its own in perpetuity without us involved.

So why did we cull this in the end design? The answer is that while it was a great step towards the system being a self-serving public good, it also was a worse user experience. It required that after researchers verify their papers, they then attain from us an ERC1155 NFT. They could use this NFT to issue a claim on the accumulated tokens due to their paper. This was nice in the abstract because it means that all of their unclaimed tokens could accumulate at the NFT, then we could just send them the NFT upon (ideally automated) verification and they could handle the remaining step. However, it was not a good experience for researchers who 99% of the time just want the funding and recognition, but not the hassle. They would rather just be given their tokens, which we can do in a batch send assuming the accounting is taken care of. We handle that accounting with an IPFS trail that’s extended with each mint.

Amaranth Prize: Powered by Research Portfolio

The Amaranth Prize is our first go at implementing research prizes on the blockchain. Supported by the Amaranth Foundation, it rewards a subset of Longevity - protein aging - with $250k in retrospective funding. This incredibly important area of study is underserved through normal channels and we’re extremely proud to be able to support it on our platform.

The process was thorough. We brought together a panel of experts in the field spearheaded by Dr. Aaron Cravens, which also included esteemed Professors Claudio Hetz, Collin Ewald, Evan Williams, and Vincent Monnier. We then aggregated more than 3,000 papers in the domain since 2015 before adding any papers that our panel deemed to also be worthy, and then collectively pared those down to a shortlist. We trimmed this shortlist down further, concluding with our incredibly deserving fifteen selected winners. These are listed prominently at the Amaranth Prize website and below in their entirety. Of them, fourteen graciously accepted while one humbly declined the prize money.

While doing this, we learned a hell of a lot on how to manage this process. Our plan from here forward is to a) ensure that the recipients receive their rewards, b) onboard parent papers, and then figure out how to more scalably support other prizes and challenges.

If you are one of those parent papers, contact us at support@researchportfolio.co to ensure that you receive your due funding.

Winning Papers

Protein carbamylation is a hallmark of aging (10.1073/pnas.1517096113) Abstract: Aging is a progressive process determined by genetic and acquired factors. Among the latter are the chemical reactions referred to as nonenzymatic posttranslational modifications (NEPTMs), such as glycoxidation, which are responsible for protein molecular aging. Carbamylation is a more recently described NEPTM that is caused by the nonenzymatic binding of isocyanate derived from urea dissociation or myeloperoxidase-mediated catabolism of thiocyanate to free amino groups of proteins. This modification is considered an adverse reaction, because it induces alterations of protein and cell properties. It has been shown that carbamylated proteins increase in plasma and tissues during chronic kidney disease and are associated with deleterious clinical outcomes, but nothing is known to date about tissue protein carbamylation during aging. To address this issue, we evaluated homocitrulline rate, the most characteristic carbamylation-derived product (CDP), over time in skin of mammalian species with different life expectancies. Our results show that carbamylation occurs throughout the whole lifespan and leads to tissue accumulation of carbamylated proteins. Because of their remarkably long half-life, matrix proteins, like type I collagen and elastin, are preferential targets. Interestingly, the accumulation rate of CDPs is inversely correlated with longevity, suggesting the occurrence of still unidentified protective mechanisms. In addition, homocitrulline accumulates more intensely than carboxymethyl-lysine, one of the major advanced glycation end products, suggesting the prominent role of carbamylation over glycoxidation reactions in age-related tissue alterations. Thus, protein carbamylation may be considered a hallmark of aging in mammalian species that may significantly contribute in the structural and functional tissue damages encountered during aging. Authors: Christine Pietrement, Laëtitia Gorisse, Christian E. H. Schmelzer, Laurent Debelle, Laurent Duca, Martin Köhler, Paul Fornès, Vincent Vuiblet, Philippe Gillery, Stephane Jaisson Important parent papers: 10.1073/pnas.93.1.485: 50.0/100, 10.1371/journal.pone.0082506: 30.0/100, 10.1038/nm1637: 10.0/100, 10.1074/jbc.M006700200: 10.0/100

Undulating changes in human plasma proteome profiles across the lifespan (10.1038/s41591-019-0673-2) Abstract: Aging is a predominant risk factor for several chronic diseases that limit healthspan1. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues2,3,4,5,6,7,8,9,10, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18–95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases. Authors: Benoit Lehallier, Andreas Keller, Claudio Franceschi, Daniela Berdnik, David Gate, Hanadie Yousef, Joe Verghese, Nicholas Schaum, Nir Barzilai, Patricia Moran Losada, Sanish Sathyan, Sofiya Milman, Song Eun Lee, Tibor Nanasi, Tony Wyss-Coray Important parent papers: 10.1038/nature10357: 34.0/100, 10.1038/s41586-018-0175-2: 33.0/100, 10.1371/journal.pone.0015004: 33.0/100

Proteomic atlas of the human brain in Alzheimer's disease (10.1021/acs.jproteome.9b00004) Abstract: The brain represents one of the most divergent and critical organs in the human body. Yet, it can be afflicted by a variety of neurodegenerative diseases specifically linked to aging, about which we lack a full biomolecular understanding of onset and progression, such as Alzheimer’s disease (AD). Here we provide a proteomic resource comprising nine anatomically distinct sections from three aged individuals, across a spectrum of disease progression, categorized by quantity of neurofibrillary tangles. Using state-of-the-art mass spectrometry, we identify a core brain proteome that exhibits only small variance in expression, accompanied by a group of proteins that are highly differentially expressed in individual sections and broader regions. AD affected tissue exhibited slightly elevated levels of tau protein with similar relative expression to factors associated with the AD pathology. Substantial differences were identified between previous proteomic studies of mature adult brains and our aged cohort. Our findings suggest considerable value in examining specifically the brain proteome of aged human populations from a multiregional perspective. This resource can serve as a guide, as well as a point of reference for how specific regions of the brain are affected by aging and neurodegeneration. Authors: Justin McKetney, Alexander S. Hebert, Rosalyn M. Runde, Shahriar Salamat, Subhojit Roy, Joshua J Coon Important parent papers: 10.1038/s41593-017-0011-2: 40.0/100, 10.1038/nature11405: 20.0/100, 10.1038/nature10523: 15.0/100, 10.1038/sdata.2018.36: 15.0/100, 10.1038/nature05453: 10.0/100

Vitamin C is a source of oxoaldehyde and glycative stress in age-related cataract and neurodegenerative diseases (10.1111/acel.13176) Abstract: Oxoaldehyde stress has recently emerged as a major source of tissue damage in aging and age-related diseases. The prevailing mechanism involves methylglyoxal production during glycolysis and modification of arginine residues through the formation of methylglyoxal hydroimidazolones (MG-H1). We now tested the hypothesis that oxidation of vitamin C (ascorbic acid or ASA) contributes to this damage when the homeostatic redox balance is disrupted especially in ASA-rich tissues such as the eye lens and brain. MG-H1 measured by liquid chromatography mass spectrometry is several fold increased in the lens and brain from transgenic mice expressing human vitamin C transporter 2 (hSVCT2). Similarly, MG-H1 levels are increased two- to fourfold in hippocampus extracts from individuals with Alzheimer's disease (AD), and significantly higher levels are present in sarkosyl-insoluble tissue fractions from AD brain proteins than in the soluble fractions. Moreover, immunostaining with antibodies against methylglyoxal hydroimidazolones reveals similar increase in substantia nigra neurons from individuals with Parkinson's disease. Results from an in vitro incubation experiment suggest that accumulated catalytic metal ions in the hippocampus during aging could readily accelerate ASA oxidation and such acceleration was significantly enhanced in AD. Modeling studies and intraventricular injection of 13C-labeled ASA revealed that ASA backbone carbons 4–6 are incorporated into MG-H1 both in vitro and in vivo, likely via a glyceraldehyde precursor. We propose that drugs that prevent oxoaldehyde stress or excessive ASA oxidation may protect against age-related cataract and neurodegenerative diseases. Authors: Xingjun Fan, Benlian Wang, Caili Hao, Daniel W. Wesson, David R. Sell, Fiona E. Harrison, Sabrina Liu, Sandra Siedlak, Terrance J. Kavanagh, Xiongwei Zhu, Vincent M Monnier Important parent papers: 10.1002/anie.201300399: 75.0/100, 10.1016/j.bbrc.2015.01.140: 25.0/100

Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation (10.2337/db16-0153) Abstract: Risk of insulin resistance, impaired glycemic control, and cardiovascular disease is excessive in overweight and obese populations. We hypothesized that increasing expression of glyoxalase 1 (Glo1)—an enzyme that catalyzes the metabolism of reactive metabolite and glycating agent methylglyoxal—may improve metabolic and vascular health. Dietary bioactive compounds were screened for Glo1 inducer activity in a functional reporter assay, hits were confirmed in cell culture, and an optimized Glo1 inducer formulation was evaluated in a randomized, placebo-controlled crossover clinical trial in 29 overweight and obese subjects. We found trans-resveratrol (tRES) and hesperetin (HESP), at concentrations achieved clinically, synergized to increase Glo1 expression. In highly overweight subjects (BMI >27.5 kg/m2), tRES-HESP coformulation increased expression and activity of Glo1 (27%, P < 0.05) and decreased plasma methylglyoxal (−37%, P < 0.05) and total body methylglyoxal-protein glycation (−14%, P < 0.01). It decreased fasting and postprandial plasma glucose (−5%, P < 0.01, and −8%, P < 0.03, respectively), increased oral glucose insulin sensitivity index (42 mL ⋅ min−1 ⋅ m−2, P < 0.02), and improved arterial dilatation Δbrachial artery flow-mediated dilatation/Δdilation response to glyceryl nitrate (95% CI 0.13–2.11). In all subjects, it decreased vascular inflammation marker soluble intercellular adhesion molecule-1 (−10%, P < 0.01). In previous clinical evaluations, tRES and HESP individually were ineffective. tRES-HESP coformulation could be a suitable treatment for improved metabolic and vascular health in overweight and obese populations. Authors: Martin O. Weickert, Mingzhan Xue, Alaa Shafie, Attia Anwar, David Messenger, Gail Jenkins, Mark Fowler, Molly Waldron, Naila Rabbani, Ngianga-Bakwin Kandala, Sheharyar Qureshi, Paul J Thornalley Important parent papers: 10.1042/BJ20111648: 70.0/100, 10.1007/s00125-005-1941-x: 15.0/100, 10.1089/ars.2014.5962: 15.0/100

Personal aging markers and ageotypes revealed by deep longitudinal profiling (10.1038/s41591-019-0719-5) Abstract: The molecular changes that occur with aging are not well understood. Here, we performed longitudinal and deep multiomics profiling of 106 healthy individuals from 29 to 75 years of age and examined how different types of ‘omic’ measurements, including transcripts, proteins, metabolites, cytokines, microbes and clinical laboratory values, correlate with age. We identified both known and new markers that associated with age, as well as distinct molecular patterns of aging in insulin-resistant as compared to insulin-sensitive individuals. In a longitudinal setting, we identified personal aging markers whose levels changed over a short time frame of 2–3 years. Further, we defined different types of aging patterns in different individuals, termed ‘ageotypes’, on the basis of the types of molecular pathways that changed over time in a given individual. Ageotypes may provide a molecular assessment of personal aging, reflective of personal lifestyle and medical history, that may ultimately be useful in monitoring and intervening in the aging process. Authors: Sara Ahadi, Wenyu Zhou, Anne Brunet, Kévin Contrepois, M. Reza Sailani, Melanie Ashland, Monika Avina, Sophia Miryam Schüssler-Fiorenza Rose, Michael Snyder Important parent papers: 10.1016/j.cell.2012.02.009: 25.0/100, 10.1038/s41586-019-1236-x: 25.0/100, 10.1186/gb-2013-14-10-r115: 25.0/100, 10.1371/journal.pmed.1002718: 25.0/100

Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans (10.1111/acel.13290) Abstract: l Using samples from the New England Centenarian Study (NECS), we sought to characterize the serum proteome of 77 centenarians, 82 centenarians' offspring, and 65 age-matched controls of the offspring (mean ages: 105, 80, and 79 years). We identified 1312 proteins that significantly differ between centenarians and their offspring and controls (FDR < 1%), and two different protein signatures that predict longer survival in centenarians and in younger people. By comparing the centenarian signature with 2 independent proteomic studies of aging, we replicated the association of 484 proteins of aging and we identified two serum protein signatures that are specific of extreme old age. The data suggest that centenarians acquire similar aging signatures as seen in younger cohorts that have short survival periods, suggesting that they do not escape normal aging markers, but rather acquire them much later than usual. For example, centenarian signatures are significantly enriched for senescence-associated secretory phenotypes, consistent with those seen with younger aged individuals, and from this finding, we provide a new list of serum proteins that can be used to measure cellular senescence. Protein co-expression network analysis suggests that a small number of biological drivers may regulate aging and extreme longevity, and that changes in gene regulation may be important to reach extreme old age. This centenarian study thus provides additional signatures that can be used to measure aging and provides specific circulating biomarkers of healthy aging and longevity, suggesting potential mechanisms that could help prolong health and support longevity. Authors: Paola Sebastiani, Anastasia Gurinovich, Anthony Federico, Catherine Costello, David Glass, Gerald Denis, Kevin Chandler, Lori Jennings, Luigi Ferrucci, Melody Morris, Stacy Andersen, Stefano Monti, Toshiko Tanaka, Thomas Perls Important parent papers: 10.1093/gerona/glr223: 70.0/100, 10.1007/s11357-018-0046-7: 20.0/100, 10.1111/acel.12799: 10.0/100

Role of Carbonyl Modifications on Aging-Associated Protein Aggregation (10.1038/srep19311) Abstract: Protein aggregation is a common biological phenomenon, observed in different physiological and pathological conditions. Decreased protein solubility and a tendency to aggregate is also observed during physiological aging but the causes are currently unknown. Herein we performed a biophysical separation of aging-related high molecular weight aggregates, isolated from the bone marrow and splenic cells of aging mice and followed by biochemical and mass spectrometric analysis. The analysis indicated that compared to younger mice an increase in protein post-translational carbonylation was observed. The causative role of these modifications in inducing protein misfolding and aggregation was determined by inducing carbonyl stress in young mice, which recapitulated the increased protein aggregation observed in old mice. Altogether our analysis indicates that oxidative stress-related post-translational modifications accumulate in the aging proteome and are responsible for increased protein aggregation and altered cell proteostasis. Authors: Maya Tanase, Aleksandra M Urbanska, Barbara Roda, Carlo Follo, Cristina C Clement, Kateryna Morozova, Liling Huang, Michael Goldberg, Pierluigi Reschiglian, Valerio Zolla, Laura Santambrogio Important parent papers: 10.1016/j.celrep.2012.06.005: 70.0/100, 10.1126/science.292.5521.1552: 30.0/100

Single Muscle Fiber Proteomics Reveals Fiber-Type-Specific Features of Human Muscle Aging (10.1016/j.celrep.2017.05.054) Abstract: Skeletal muscle is a key tissue in human aging, which affects different muscle fiber types unequally. We developed a highly sensitive single muscle fiber proteomics workflow to study human aging and show that the senescence of slow and fast muscle fibers is characterized by diverging metabolic and protein quality control adaptations. Whereas mitochondrial content declines with aging in both fiber types, glycolysis and glycogen metabolism are upregulated in slow but downregulated in fast muscle fibers. Aging mitochondria decrease expression of the redox enzyme monoamine oxidase A. Slow fibers upregulate a subset of actin and myosin chaperones, whereas an opposite change happens in fast fibers. These changes in metabolism and sarcomere quality control may be related to the ability of slow, but not fast, muscle fibers to maintain their mass during aging. We conclude that single muscle fiber analysis by proteomics can elucidate pathophysiology in a sub-type-specific manner. Authors: Marta Murgia, Carlo Reggiani, Luana Toniolo, Nagarjuna Nagaraj, Stefano Ciciliot, Stefano Schiaffino, Vincenzo Vindigni, Matthias Mann Important parent papers: 10.1038/nmeth.2834: 30.0/100, 10.1152/physrev.00031: 30.0/100, 10.1111/acel.12153: 20.0/100, 10.1152/japplphysiol.00905: 20.0/100

Knockout of receptor for advanced glycation end-products attenuates age-related renal lesions (10.1111/acel.12850) Abstract: Pro-aging effects of endogenous advanced glycation end-products (AGEs) have been reported, and there is increasing interest in the pro-inflammatory and -fibrotic effects of their binding to RAGE (the main AGE receptor). The role of dietary AGEs in aging remains ill-defined, but the predominantly renal accumulation of dietary carboxymethyllysine (CML) suggests the kidneys may be particularly affected. We studied the impact of RAGE invalidation and a CML-enriched diet on renal aging. Two-month-old male, wild-type (WT) and RAGE−/− C57Bl/6 mice were fed a control or a CML-enriched diet (200 μg CML/gfood) for 18 months. Compared to controls, we observed higher CML levels in the kidneys of both CML WT and CML RAGE−/− mice, with a predominantly tubular localization. The CML-rich diet had no significant impact on the studied renal parameters, whereby only a trend to worsening glomerular sclerosis was detected. Irrespective of diet, RAGE−/− mice were significantly protected against nephrosclerosis lesions (hyalinosis, tubular atrophy, fibrosis and glomerular sclerosis) and renal senile apolipoprotein A-II (ApoA-II) amyloidosis (p < 0.001). A positive linear correlation between sclerosis score and ApoA-II amyloidosis score (r = 0.92) was observed. Compared with old WT mice, old RAGE−/− mice exhibited lower expression of inflammation markers and activation of AKT, and greater expression of Sod2 and SIRT1. Overall, nephrosclerosis lesions and senile amyloidosis were significantly reduced in RAGE−/− mice, indicating a protective effect of RAGE deletion with respect to renal aging. This could be due to reduced inflammation and oxidative stress in RAGE−/− mice, suggesting RAGE is an important receptor in so-called inflamm-aging. Authors: Thibault Teissier, Valentine Quersin, Ann-Marie Schmidt, Chantal Fradin, Christelle Cauffiez, Cécile Lemoine, Florian Delguste, François Glowacki, Frédéric J. Tessier, Maité Daroux, Mike Howsam, Thierry Brousseau, Viviane Gnemmi, Eric Boulanger, Marie Frimat Important parent papers: 10.1002/mnfr.201400643: 35.0/100, 10.1002/mnfr.201600140: 35.0/100, 10.1517/14728222.2016.1111873: 30.0/100

RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity (10.1172/JCI85210) Abstract: Islet amyloidosis is characterized by the aberrant accumulation of islet amyloid polypeptide (IAPP) in pancreatic islets, resulting in β cell toxicity, which exacerbates type 2 diabetes and islet transplant failure. It is not fully clear how IAPP induces cellular stress or how IAPP-induced toxicity can be prevented or treated. We recently defined the properties of toxic IAPP species. Here, we have identified a receptor-mediated mechanism of islet amyloidosis–induced proteotoxicity. In human diabetic pancreas and in cellular and mouse models of islet amyloidosis, increased expression of the receptor for advanced glycation endproducts (RAGE) correlated with human IAPP–induced (h-IAPP–induced) β cell and islet inflammation, toxicity, and apoptosis. RAGE selectively bound toxic intermediates, but not nontoxic forms of h-IAPP, including amyloid fibrils. The isolated extracellular ligand–binding domains of soluble RAGE (sRAGE) blocked both h-IAPP toxicity and amyloid formation. Inhibition of the interaction between h-IAPP and RAGE by sRAGE, RAGE-blocking antibodies, or genetic RAGE deletion protected pancreatic islets, β cells, and smooth muscle cells from h-IAPP–induced inflammation and metabolic dysfunction. sRAGE-treated h-IAPP Tg mice were protected from amyloid deposition, loss of β cell area, β cell inflammation, stress, apoptosis, and glucose intolerance. These findings establish RAGE as a mediator of IAPP-induced toxicity and suggest that targeting the IAPP/RAGE axis is a potential strategy to mitigate this source of β cell dysfunction in metabolic disease. Authors: Andisheh Abedini, Annette Plesner, Fei Song, Huilin Li, Hyunwook Koh, Jacqueline Lonier, Jinghua Zhang, Julia Derk, Meilun He, Ping Cao, Rosa Rosario, Sachi A. Patil, Ann Marie Schmidt, Daniel P. Raleigh Important parent papers: 10.7554/eLife.12977: 80.0/100, 10.1073/pnas.0909024107: 10.0/100, 10.1155/2016/2798269: 10.0/100

Cyanate-Impaired Angiogenesis: Association With Poor Coronary Collateral Growth in Patients With Stable Angina and Chronic Total Occlusion (10.1161/JAHA.116.004700) Abstract: In this study, we demonstrated that oral administration of cyanate impaired blood perfusion recovery in a mouse hind‐limb ischemia model. A reduction in blood perfusion recovery at day 21 was observed in the ischemic tissue of cyanate‐treated mice. Likewise, there were fewer capillaries in the ischemic hind‐limb tissue of cyanate‐exposed mice. Our in vitro study showed that cyanate, together with its carbamylated products, inhibited the migration, proliferation, and tube‐formation abilities of endothelial cells. Further research revealed that cyanate regulated angiogenesis partly by interrupting the vascular endothelial growth factor receptor 2/phosphatidylinositol 3‐kinase/Akt pathway. The serum concentrations of homocitrulline, a marker of cyanate exposure, were determined in 117 patients with stable angina and chronic total occlusion. Consistent with the antiangiogenic role of cyanate, homocitrulline levels were increased in patients with poor coronary collateralization (n=58) compared with those with high collateralization (n=59; 21.09±13.08 versus 15.54±9.02 ng/mL, P=0.009). In addition, elevated homocitrulline concentration was a strong predictor of poor coronary collateral growth. Authors: Jia Teng Sun, Jing Yan Mao, Ke Yang, Li Ping Wu, Lin Lu, Qi Hong Wu, Wei Feng Shen, Yan Ping Wang, Rui Yan Zhang Important parent papers: 10.1038/nm1637: 40.0/100, 10.1126/scitranslmed.3005218: 30.0/100, 10.1681/ASN.2010040365: 30.0/100

Plasma proteomic biomarker signature of age predicts health and life span (10.7554/eLife.61073) Abstract: Older age is a strong shared risk factor for many chronic diseases, and there is increasing interest in identifying aging biomarkers. Here, a proteomic analysis of 1301 plasma proteins was conducted in 997 individuals between 21 and 102 years of age. We identified 651 proteins associated with age (506 over-represented, 145 underrepresented with age). Mediation analysis suggested a role for partial cis-epigenetic control of protein expression with age. Of the age-associated proteins, 33.5% and 45.3%, were associated with mortality and multimorbidity, respectively. There was enrichment of proteins associated with inflammation and extracellular matrix as well as senescence-associated secretory proteins. A 76-protein proteomic age signature predicted accumulation of chronic diseases and all-cause mortality. These data support the use of proteomic biomarkers to monitor aging trajectories and to identify individuals at higher risk of disease to be targeted for in depth diagnostic procedures and early interventions. Authors: Toshiko Tanaka, Angelique Biancotto, Ann Z Moore, Birgit Schilling, Giovanna Fantoni, Julián Candia, Nathan Basisty, Luigi Ferrucci, Stefania Bandinelli Important parent papers: 10.1111/acel.12799: 50.0/100, 10.1038/s41586-018-0175-2: 25.0/100, 10.1038/s41591-019-0673-2: 25.0/100

Constant molecular aging rates vs the exponential acceleration of mortality. (10.1073/pnas.1524017113) Abstract: No abstract available Authors: Caleb E Finch, Eileen Crimmins Important parent papers: 10.1073/pnas.93.1.485: 40.0/100, 10.1073/pnas.1517096113: 30.0/100, 10.1159/000357672: 30.0/100

Protein carbamylation exacerbates vascular calcification.

Abstract: Protein carbamylation is a posttranslational modification that can occur non-enzymatically in the presence of high concentrations of urea. Although carbamylation is recognized as a prognostic biomarker, the contribution of protein carbamylation to organ dysfunction remains uncertain. Because vascular calcification is common under carbamylation-prone situations, we investigated the effects of carbamylation on this pathologic condition. Protein carbamylation exacerbated the calcification of human vascular smooth muscle cells (hVSMCs) by suppressing the expression of ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1), a key enzyme in the generation of pyrophosphate, which is a potent inhibitor of ectopic calcification. Several mitochondrial proteins were carbamylated, although ENPP1 itself was not identified as a carbamylated protein. Rather, protein carbamylation reduced mitochondrial membrane potential and exaggerated mitochondria-derived oxidative stress, which down-regulated ENPP1. The effects of carbamylation on ectopic calcification were abolished in hVSMCs by ENPP1 knockdown, in mitochondrial-DNA-depleted hVSMCs, and in hVSMCs treated with a mitochondria-targeted superoxide scavenger. We also evaluated the carbamylation effects using ex vivo and in vivo models. The tunica media of a patient with end-stage renal disease was carbamylated. Thus, our findings have uncovered a previously unrecognized aspect of uremia-related vascular pathology.

Authors: Daisuke Mori, I. Matsui, Akihiro Shimomura, Nobuhiro Hashimoto, Ayumi Matsumoto, Karin Shimada, Satoshi Yamaguchi, Tatsufumi Oka, Keiichi Kubota, S. Yonemoto, Y. Sakaguchi, Atsushi Takahashi, Y. Shintani, S. Takashima, Y. Takabatake, T. Hamano, Y. Isaka

Thank you

Nothing like this is accomplished without a village. While Adam and I built Research Portfolio to today’s milestone, we were aided along the way by fantastic people who gave their time and energy.

These include Yi Sun (Axiom), Tyler Gordon (BigBinary), Will Wolf (Gauntlet), Aayush Gupta (ZKEmail), Will Whitney (DeepMind), Vincent Weisser (Molecule), Evan Miyazano (Protocol Labs), Darren Zhu (Atoms), Curtis Spencer & Avichal Garg (Electric Capital), Jess Lin (Musician, Writer, Friend), Michael McCanna (Immunefi), Shazow (Crisis), and Brent (Crisis).

These also include organizations. Immunefi and Composable Security were clutch in helping us vet the security of the contracts. Privy’s embedded wallet solution was exceptionally timely. And Studio Rodriguez was instrumental in helping with design.

Most of all, thank you to the Amaranth Foundation and to Blueprint Forest for your ongoing and generous support.