Tom Roseberry

Aging remains a challenging biological process to quantify. Designing effective aging therapeutics hinges on the ability to reliably measure it.

One promising strategy is assessing age-related changes to the 3D structure of DNA. 

quantify these structural changes, using them as inputs to predict the biological age of the tissue.

In addition to the nucleotide sequence, the 3D structure of a DNA strand holds valuable information, too. The most common structural change to DNA is 

 – the addition of a methyl group to a cytosine base at a cytosine/guanine nucleotide pair (

). Methylation changes the shape, and therefore the function, of certain areas of DNA; the methylation status of certain CpG sites change predictably with age.

These changes can be used to create epigenetic “clocks” to quantify the age of an animal or tissue. Just like DNA, methylation can be easily and cheaply sequenced. Different epigenetic clocks weight different combinations of CpG sites, often 1000s, to calculate the predicted age of an animal or tissue.

The use of epigenetics in aging drug development

Loyal is developing drugs intended to extend lifespan (years of life) and healthspan (quality of life). However, it inevitably takes years to determine whether a potential aging drug actually impacts the aging process. Epigenetic clocks may allow one to predict the efficacy (or lack thereof) of a novel aging drug potentially years before measurable changes in healthspan and lifespan.

Put simply, a reliable epigenetic clock may help us understand if an animal is aging quickly or slowly in relation to its peers, and whether a specific intervention has affected that rate of aging.

Loyal has licensed a novel clock and methodology from the Ideker Group at The University of California, San Diego.

This clock identified aging-relevant CpG sites that are conserved between mice, dogs and humans, laying the foundations for conserved aging quantification. In their Cell Systems publication[1], the Ideker Group showed that their epigenetic clock can determine, within one year, the chronological age of a dog. The paper also proposes a more accurate conversion of dog and human years, especially relevant given Loyal’s thesis that developing dog aging drugs will be a key step to developing human aging drugs.

In addition to determining the chronological age of a dog – especially important in the case of shelter dogs and others without birth records – this work out of the Ideker group may help:

In addition, Loyal has partnered with the Morris Animal Foundation to investigate the potential use of DNA methylation changes to predict cancer onset in Golden Retrievers [2].

B-cell lymphoma and hemangiosarcoma are the leading causes of death in Goldens; earlier detection and therefore intervention could result in longer, happier lives for this breed. Additionally, understanding conserved risk-factors for age-related cancers may help identify potential drug development targets for both Goldens and humans.

Most of the methodology for building epigenetic clocks has involved using basic linear regressions and simple representations of methylation as single numbers. Loyal is leveraging the latest machine and deep learning models – in addition to representations of genomic data gleaned from natural language processing algorithms – to access the full richness of information available within the epigenome. We believe this will yield insights beyond age measurement and provide a more holistic view of the aging organism.

Quantifying the Aging Process: Loyal in-licenses mouse-canine-human homogeneous epigenetic clock from UCSD

Aging remains a challenging biological process to quantify. Designing effective aging therapeutics hinges on the ability to reliably measure it.



One promising strategy is assessing age-related changes to the 3D structure of DNA. Epigenetic clocks quantify these structural changes, using them as inputs to predict the biological age of the tissue.



<h2 class="wp-block-heading">Epigenetics 101</h2>



In addition to the nucleotide sequence, the 3D structure of a DNA strand holds valuable information, too. The most common structural change to DNA is&nbsp;methylation&nbsp;&#8211; the addition of a methyl group to a cytosine base at a cytosine/guanine nucleotide pair (CpG site). Methylation changes the shape, and therefore the function, of certain areas of DNA; the methylation status of certain CpG sites change predictably with age.



These changes can be used to create epigenetic “clocks” to quantify the age of an animal or tissue. Just like DNA, methylation can be easily and cheaply sequenced. Different epigenetic clocks weight different combinations of CpG sites, often 1000s, to calculate the predicted age of an animal or tissue.







<h2 class="wp-block-heading">The use of epigenetics in aging drug development</h2>



Loyal is developing drugs intended to extend lifespan (years of life) and healthspan (quality of life). However, it inevitably takes years to determine whether a potential aging drug actually impacts the aging process. Epigenetic clocks may allow one to predict the efficacy (or lack thereof) of a novel aging drug potentially years before measurable changes in healthspan and lifespan.



Put simply, a reliable epigenetic clock may help us understand if an animal is aging quickly or slowly in relation to its peers, and whether a specific intervention has affected that rate of aging.







<h2 class="wp-block-heading">Loyal has licensed a novel clock and methodology from the Ideker Group at The University of California, San Diego.</h2>



This clock identified aging-relevant CpG sites that are conserved between mice, dogs and humans, laying the foundations for conserved aging quantification. In their Cell Systems publication[1], the Ideker Group showed that their epigenetic clock can determine, within one year, the chronological age of a dog. The paper also proposes a more accurate conversion of dog and human years, especially relevant given Loyal’s thesis that developing dog aging drugs will be a key step to developing human aging drugs.



In addition to determining the chronological age of a dog &#8211; especially important in the case of shelter dogs and others without birth records &#8211; this work out of the Ideker group may help:



<ul class="wp-block-list">
<li>Provide early evidence for potential future customers that an aging treatment is indeed slowing or reversing the aging process in their dog.</li>



<li>Speed up drug development iteration by use as a surrogate endpoint/aging biomarker in clinical trials.</li>



<li>Point to new aging targets by studying the specific structural changes to DNA and their downstream consequences.</li>
</ul>



<figure class="wp-block-image size-large"><img loading="lazy" decoding="async" width="1024" height="757" src="https://blog-admin.loyalfordogs.com/wp-content/uploads/2024/01/wang-et-al-1024x757.webp" alt="" class="wp-image-972" srcset="https://blog-admin.loyalfordogs.com/wp-content/uploads/2024/01/wang-et-al-1024x757.webp 1024w, https://blog-admin.loyalfordogs.com/wp-content/uploads/2024/01/wang-et-al-300x222.webp 300w, https://blog-admin.loyalfordogs.com/wp-content/uploads/2024/01/wang-et-al-768x568.webp 768w, https://blog-admin.loyalfordogs.com/wp-content/uploads/2024/01/wang-et-al.webp 1402w" sizes="(max-width: 1024px) 100vw, 1024px" /></figure>



<h2 class="wp-block-heading">In addition, Loyal has partnered with the Morris Animal Foundation to investigate the potential use of DNA methylation changes to predict cancer onset in Golden Retrievers [2].</h2>



B-cell lymphoma and hemangiosarcoma are the leading causes of death in Goldens; earlier detection and therefore intervention could result in longer, happier lives for this breed. Additionally, understanding conserved risk-factors for age-related cancers may help identify potential drug development targets for both Goldens and humans.



Most of the methodology for building epigenetic clocks has involved using basic linear regressions and simple representations of methylation as single numbers. Loyal is leveraging the latest machine and deep learning models &#8211; in addition to representations of genomic data gleaned from natural language processing algorithms &#8211; to access the full richness of information available within the epigenome. We believe this will yield insights beyond age measurement and provide a more holistic view of the aging organism.



<ol class="wp-block-list">
<li>Wang T et al. Quantitative Translation of Dog-to-Human Aging by Conserved Remodeling of the DNA Methylome. Cell Syst. 2020 Aug 26;11(2):176-185.e6. doi: 10.1016/j.cels.2020.06.006.</li>



<li>Morris Animal Foundation Partners with Loyal to Study Dogs’ Genetic Changes that Occur as They Age. June 7, 2021.&nbsp;<a href="https://www.morrisanimalfoundation.org/article/loyal-dog-aging-study-golden-retriever" rel="noreferrer noopener" target="_blank">https://www.morrisanimalfoundation.org/article/loyal-dog-aging-study-golden-retriever</a>.</li>
</ol>

Michael LaCroix-Fralish

Assessing whether or not a candidate drug increases lifespan in animals requires a great deal of planning and control. Any number of external factors can result in spurious results in a longevity study that can take 3+ years to perform. The best study is one that is carefully standardized to minimize these external factors

The Interventions Testing Program (ITP) is the standard in controlled longevity studies

The National Institute on Aging (NIA) is a division of the United States National Institutes of Health (NIH). Founded in 1974, the 

 is a national center of leadership and expertise on biology of aging research; In order to standardize the process of testing compounds for pro-longevity properties, the NIA has established the The Interventions Testing Program (ITP).

The ITP program uses a rigorous protocol to test compounds across three separate research institutions (University of Michigan, the Jackson Laboratories, and the University of Texas Health Sciences Center at San Antonio) using the same type of mice to ensure that the findings are robust and reproducible. [1] Over the past 17 years, the ITP has proven to be the gold standard by which potential pro-longevity compounds are evaluated, having identified seven new compounds that significantly increase lifespan in mice. A detailed introduction to the strategy behind the ITP can be found in paper by Warner, et al. [2]

ITP projects are nominated by external investigators and are rigorously vetted by a team of esteemed experts in the aging research field for the potential to extend lifespan and delay disease and dysfunction in mice. Only compounds backed by the strongest scientific ideas get approval to join the ITP program.

Due to this rigorous vetting process, the ITP has historically accepted only four or five new interventions for investigation each year.

For the 2021 cohort, we are proud to announce that two Loyal-sponsored compound proposals were accepted for the ITP program.

Loyal is committed to contributing to the fundamental biological understanding of aging and investigating novel targets for improving lifespan and healthspan. The selected compounds that our team nominated this year will help the aging research field to better understand two new targets/mechanisms that have the potential to significantly increase healthy lifespan.

Through this research collaboration with the NIA ITP we continue to make significant progress in our mission of identifying novel approaches to improve the healthy lives of dogs. We are excited by the opportunity to work with the exceptional scientists at the ITP to test these important new ideas.

Two Loyal-nominated compounds selected for the National Institute on Aging Interventions Testing Program

Assessing whether or not a candidate drug increases lifespan in animals requires a great deal of planning and control. Any number of external factors can result in spurious results in a longevity study that can take 3+ years to perform. The best study is one that is carefully standardized to minimize these external factors







The Interventions Testing Program (ITP) is the standard in controlled longevity studies







The National Institute on Aging (NIA) is a division of the United States National Institutes of Health (NIH). Founded in 1974, the <a href="https://www.nia.nih.gov/" target="_blank" rel="noreferrer noopener">NIA</a> is a national center of leadership and expertise on biology of aging research; In order to standardize the process of testing compounds for pro-longevity properties, the NIA has established the The Interventions Testing Program (ITP).



The ITP program uses a rigorous protocol to test compounds across three separate research institutions (University of Michigan, the Jackson Laboratories, and the University of Texas Health Sciences Center at San Antonio) using the same type of mice to ensure that the findings are robust and reproducible. [1] Over the past 17 years, the ITP has proven to be the gold standard by which potential pro-longevity compounds are evaluated, having identified seven new compounds that significantly increase lifespan in mice. A detailed introduction to the strategy behind the ITP can be found in paper by Warner, et al. [2]



ITP projects are nominated by external investigators and are rigorously vetted by a team of esteemed experts in the aging research field for the potential to extend lifespan and delay disease and dysfunction in mice. Only compounds backed by the strongest scientific ideas get approval to join the ITP program.



Due to this rigorous vetting process, the ITP has historically accepted only four or five new interventions for investigation each year.







<h2 class="wp-block-heading">For the 2021 cohort, we are proud to announce that two Loyal-sponsored compound proposals were accepted for the ITP program.</h2>



Loyal is committed to contributing to the fundamental biological understanding of aging and investigating novel targets for improving lifespan and healthspan. The selected compounds that our team nominated this year will help the aging research field to better understand two new targets/mechanisms that have the potential to significantly increase healthy lifespan.



Through this research collaboration with the NIA ITP we continue to make significant progress in our mission of identifying novel approaches to improve the healthy lives of dogs. We are excited by the opportunity to work with the exceptional scientists at the ITP to test these important new ideas.



<ol class="wp-block-list">
<li><a href="https://www.nia.nih.gov/research/dab/interventions-testing-program-itp" target="_blank" rel="noreferrer noopener">https://www.nia.nih.gov/research/dab/interventions-testing-program-itp</a></li>



<li>Mechanisms of Ageing and Development, 115: 199–207, 2000</li>
</ol>

Celine Halioua

I’m excited to share that Blake Scholl, the Founder and CEO of 

, has joined our Board of Directors as our first Independent Director.

Blake’s deep expertise in building and scaling a successful, mission-driven business within a highly regulated industry will be both instructive and valuable for Loyal as we grow. 

Loyal hit a number of key milestones over the last twelve months for LOY001 (an implant for large dog lifespan extension) and LOY002 (a daily, tasty pill for old dog lifespan extension):

We are running towards hopeful FDA approval of our drug programs, and being able to support veterinarians and pet parents in helping their dogs live longer, healthier lives.

Blake’s operational, commercial, and technical expertise brings immense benefit as we build towards bringing the first dog aging drugs to market.  

We’re delighted he’s joining our Board.

Blake Scholl joins the Loyal Board of Directors

I’m excited to share that Blake Scholl, the Founder and CEO of <a href="https://boomsupersonic.com/">Boom Supersonic</a>, has joined our Board of Directors as our first Independent Director.



Blake’s deep expertise in building and scaling a successful, mission-driven business within a highly regulated industry will be both instructive and valuable for Loyal as we grow.&nbsp;



Loyal hit a number of key milestones over the last twelve months for LOY001 (an implant for large dog lifespan extension) and LOY002 (a daily, tasty pill for old dog lifespan extension):



<ul class="wp-block-list"><li>We dosed the first companion dog — Josie, a seven-year-old Mastiff — with one of our aging drugs.</li><li>We manufactured prototypes of LOY001 and LOY002.</li><li>We successfully completed the canine aging efficacy data for our two current drug programs, and submitted the LOY001 efficacy package to the FDA.</li><li>We have over 50 veterinary practices interested in participating in our clinical study of LOY002.</li></ul>



We are running towards hopeful FDA approval of our drug programs, and being able to support veterinarians and pet parents in helping their dogs live longer, healthier lives.



Blake’s operational, commercial, and technical expertise brings immense benefit as we build towards bringing the first dog aging drugs to market.&nbsp;&nbsp;



We’re delighted he’s joining our Board.