Animals carry "mutational clocks" in their cells that dictate how quickly their DNA picks up mutations. And across species, animals tend to die once they've hit a certain number of mutations, new research finds.
It turns out that, in long-lived mammals like humans, these mutational clocks tick slower than they do in short-lived mammals like mice, meaning humans reach that threshold number of mutations at a later age than mice do. This discovery, the researchers said, could help solve a long-standing mystery in biology.
This mystery, known as Peto's paradox, describes a perplexing phenomenon that has defied explanation since the 1970s. At that time, scientists knew that animal cells accrued mutations in their DNA over time, and that as the number of mutations increased, so too did the risk of those cells turning cancerous. On paper, this suggests that the world's longest-living and largest animals should face the highest risk of cancer, because the chance of picking up cancer-causing mutations increases over time and as the total number of cells in an organism goes up.
But oddly enough, large, long-lived animals develop cancer at similar rates as tiny, short-lived creatures this is Peto's paradox. Now, in a new study, published April 13 in the journal Nature, scientists offer a partial potential solution to this puzzle: They discovered that short- and long-lived mammals both accumulate a similar number of genetic mutations over their lifespans, but the long-lived animals do so at a far slower rate.
"I was really surprised" at the strength of the relationship between lifespan and mutation rate in different species, said Alex Cagan, a staff scientist at the Wellcome Sanger Institute in England and first author of the study. The study results help explain one aspect of Peto's paradox, by showing that having a lengthy lifespan doesn't put animals at higher risk of cancer-causing mutations. However, the authors didn't find a strong link between animals' body masses and their mutational clocks, so their results don't address the question of why big animals don't have high rates of cancer.
Related: Scientists discover 4 distinct patterns of aging
The results do support the theory that animals age, at least in part, due to the build-up of mutations in their cells over time although the study doesn't reveal exactly how the mutations contribute to the aging process, Cagan said.
"Based on our results, yes, you can tell a mammal is close to the end of its species' lifespan when it has [approximately] 3,200 mutations in its colonic epithelial stem cells," which was the specific population of cells that the team analyzed. "But we don't think that it's because at 3,201, the animal will drop dead from mutation overload," Cagan said. Rather, the authors think that the relationship between animals' mutational clocks and aging might be a bit more nuanced.
To see how quickly mutational clocks tick in different mammals, the team analyzed genetic material from 16 species: humans, black-and-white colobus monkeys, cats, cows, dogs, ferrets, giraffes, harbor porpoises, horses, lions, mice, naked mole-rats, rabbits, rats, ring-tailed lemurs and tigers. Of these species, humans have the longest lifespan at roughly 80 years; mice and rats had the shortest lifespans, between about 3 and 4 years.
From each of these species, the researchers collected DNA from "crypts," which are tiny folds found in the lining of the small intestines and colon. The cells in each crypt all descend from a single stem cell, meaning they're all clones of that stem cell. Past studies suggest that, at least in humans, crypt cells pick up mutations at a constant rate as a person ages.
In total, the researchers analyzed more than 200 crypt tissue samples from the 16 species; each sample contained a few hundred cells, Cagan noted.
"The ability to sequence the genomes of very small cell populations (e.g. those that are found within one crypt) is fairly new, so this study could not have easily been done 20 years ago," said Kamila Naxerova, an assistant professor at Harvard Medical School and a principal investigator at the Massachusetts General Hospital Center for Systems Biology, who was not involved in the study.
Related: Anti-aging vaccine shows promise in mice will it work in humans?
The team determined the total number of DNA mutations present in each sample, and by taking each animal's age into account, they were able to estimate how quickly these mutations cropped up over the organism's lifespan. In some species, including dogs, mice and cats, the team had enough samples to compare the total number of mutations in individuals of different ages for instance, a 1-year-old mouse versus a 2-year-old mouse to double-check the accuracy of their mutation rate estimates.
Through their analysis, the authors discovered that, just like in humans, the crypt cells of other mammals also accrue mutations at a constant rate, year to year. But what was striking was that this mutation rate differed drastically between species. Human crypts accumulated the lowest number of new mutations each year, at only 47, while mouse crypts picked up the most, at a whopping 796 per year.
"This difference is staggering, given the large overall similarities between human and mouse genomes," Naxerov and Alexander Gorelick, a postdoctoral fellow at Harvard Medical School and Massachusetts General Hospital, wrote in an accompanying Nature commentary on the study.
Overall, the mutation rate of each species showed an inverse correlation to its lifespan, meaning that as an animal's lifespan increased the rate of new mutations per year decreased. That ultimately meant that "the total number of mutations at the end of an animal's life was roughly similar across species," Naxerova and Gorelick noted.
The new study doesn't hint at why long-lived animals' mutational clocks tick slower than those of short-lived animals, Cagan said. That said, an earlier study, published in October 2021 in the journal Science Advances, provides one explanation.
In that study, scientists sampled fibroblasts a type of cell found in connective tissue from the lungs of mice, guinea pigs, blind mole-rats, naked mole-rats and humans and then exposed these cells to a mutagen, or a chemical that damages DNA. "Our reasoning was that cells from long-lived species may cope much better with a mutagen than cells from short-lived species," said Jan Vijg, a professor and chair of the Department of Genetics at the Albert Einstein College of Medicine and senior author of the Science Advances report.
And that's just what they found. "Cells from a short-lived mouse quickly accumulated a lot of mutations, while in the very long-lived naked mole-rat or human, the same dose of mutagen did not even induce any mutations," said Vijg, who was not involved in the new Nature study. This suggests that long-lived animals may be better at repairing DNA damage and preventing mutations than short-lived animals, and this may partially explain why they accumulate mutations at a slower rate.
One limitation of both recent studies is that they each included just one cell type intestinal crypt cells or lung fibroblasts, Vijg said. That said, analyses of additional cell types would likely turn up similar results, he said. "I would expect that the findings would generalize to most other somatic cells," meaning cells that aren't eggs or sperm, Naxerova agreed.
Related: Natural rates of aging are fixed, study suggests
Cagan and his team are launching such studies into additional tissue types now. At the same time, they're moving beyond mammals to study a wide range of vertebrates and invertebrates, to see if the same relationship holds across the animal kingdom, he said. For example, the team recently got a hold of tissue samples from a super-rare Greenland shark that washed ashore in the U.K. and may have been about 100 years old at the time of its death, he said. Scientists estimate that this species can live at least up to 272 years, Live Science previously reported.
Within that research, Cagan's team hopes to reveal how the steady accumulation of mutations actually contributes to aging assuming it does at all, Cagan said. On this front, the team has proposed a theory.
They suggest that, as all somatic cells pick up mutations over time, some of those cells will develop mutations in critical genes that would normally regulate the cells' behavior. These corrupted cells become worse at their jobs but are able to multiply more efficiently than their neighbors, the theory suggests. And as these cells take over tissues in the body, this would ultimately cause organ systems to malfunction, leading to disease and death, Cagan said.
So "it's not that every cell stops working because it's accumulated a lot of mutations," he said. Rather, problematic mutations in specific cells cause those cells to go rogue, take over tissues and crowd out all the healthier, better-functioning cells. Therefore, the mutational clock of each species likely sets the pace at which these rogue cells take over, such that "it takes a lifetime before these clonal expansions of poorly functioning cells have disrupted the tissues so much that the animal can no longer function."
Such rogue cells could be described as "selfish," since they spread to the detriment of cells around them, Naxerov and Gorelick wrote in their commentary. There's evidence from animal studies that such selfish cells can emerge in the haematopoietic system the bodily system that makes blood and drive disease by contributing to chronic inflammation, Naxerov told Live Science.
"It could be that selfish clones in other organs contribute to disease and aging as well, but I think this is largely hypothetical for now," she said.
Originally published on Live Science.
See more here:
Ticking time bombs of DNA mutation may dictate when animals die - Livescience.com
- Heres How Fasting Benefits Your Mental and Physical Wellbeing - News18 - October 4th, 2022
- Asymmetrex Gives First Cell Culture Core Facility Introduction to Online Rapid Stem Cell Counting in the Institute for Applied Life Sciences at... - September 25th, 2022
- Asymmetrex's Introduction of Online Calculators for Determination of the Dosage of Therapeutic Stem Cells Announced as a Reformation in Stem Cell... - September 16th, 2022
- UMass Dartmouth awarded $750000 Massachusetts Life Science grant to diversify the field - New Bedford Guide - September 16th, 2022
- ALS Thought Leaders Weigh in Ahead of Second Amylyx Adcomm - BioSpace - September 8th, 2022
- Scientists convert kidney to universal O blood type - Freethink - August 30th, 2022
- Case Study: SARS-CoV-2 Virus Infecting the Inner Ear - Victoria News - August 14th, 2022
- Evidence Is Growing That LSD Improves Learning and Memory - Futurism - August 14th, 2022
- Rice University: Rice, Baylor developing implants to heal heart attack injuries | India Education | Latest Education News | Global Educational News |... - August 14th, 2022
- Iconic everyday inventions and the women behind them - YourStory - August 14th, 2022
- Head to Head Analysis: VolitionRx (NYSE:VNRX) vs. Intellia Therapeutics (NASDAQ:NTLA) - Defense World - August 14th, 2022
- Man who saved life as stem cell donor urges others to help his friend find a match after five-year search - Lancashire Evening Post - August 5th, 2022
- The 3D Cell Culture Market is expected to reach a value of USD 3721.86 Million by 2027, at a CAGR of 13.4% (2021 2027) - Digital Journal - August 5th, 2022
- Flow Cytometry Market is expected to reach a value of USD 11467.80 Million by 2027, at a CAGR of 8.88% over the forecast period (2021 2027) - Digital... - July 27th, 2022
- Stem Cells Market Competitive Insights And Global Outlook 2022 To 2027 Vcanbio, Boyalife, Beikebiotech, Thermo Fisher Scientific (Massachusetts, US),... - July 11th, 2022
- Seven UMass Amherst Faculty Members Receive NSF CAREER Awards in 2021-22 Academic Year - UMass News and Media Relations - July 11th, 2022
- BrainStorm Strengthens Executive Team with Key Appointments in R&D and Legal - GuruFocus.com - June 22nd, 2022
- Asymmetrex Presents New Developments in its Rapid Stem Cell Counting Technology at the ARMI|BioFabUSA Meeting in the Millyard on Regenerative Medicine... - June 13th, 2022
- Investigators Seek to Push Combination Therapy to the Front-line Treatment of aGVHD - OncLive - June 4th, 2022
- Stem Cells Market 2022 Industry Analysis, Segmentation, Share, Size, Opportunities and Forecast to 2027 The Greater Binghamton Business Journal - The... - June 4th, 2022
- Sheldon Krimsky, Who Warned of Profit Motive in Science, Dies at 80 - The New York Times - May 15th, 2022
- We met during cancer treatments, fell in love and got married - New York Post - May 15th, 2022
- Sen. Orrin Hatch's legacy tracks the GOP's evolution on health - Wisconsin Public Radio - May 2nd, 2022
- Emerging interactions between skin stem cells and their ... - April 6th, 2022
- Priothera Receives R&D Innovation Loan from Bpifrance - PR Newswire - April 6th, 2022
- What is Regeneration? review: A dive into the science of regrowth - New Scientist - April 6th, 2022
- 5 FDA decisions to watch in the second quarter - BioPharma Dive - April 6th, 2022
- Takeda and the New York Academy of Sciences Announce 2022 Innovators in Science Award Winners - The New York Academy of Sciences - April 6th, 2022
- MorphoSys and Incyte Announce Swissmedic Temporary Approval of Minjuvi(R) (tafasitamab) in Combination with Lenalidomide for the Treatment of Adults... - March 25th, 2022
- January 2022: 2021 Papers of the year - Environmental Factor Newsletter - January 5th, 2022
- Liso-Cel Outperforms Standard Therapy in Improving QoL in Relapsed/Refractory LBCL - www.oncnursingnews.com/ - January 5th, 2022
- Stem cells: Sources, types, and uses - Medical News Today - December 24th, 2021
- cGVHD Paradigm Gains Systemic Options Beyond Steroids, But Real-World Data Are Required - OncLive - October 28th, 2021
- Asymmetrex Will Present a New Test for Therapeutic Stem Cell Potency at the ISSCR 2021 Annual Meeting - PRNewswire - June 23rd, 2021
- Infertility: Men account for at least half of cases. So why have women shouldered the blame? - The Irish Times - June 23rd, 2021
- On systemic sources of early life stress, and empathetic responses - MIT News - June 6th, 2021
- How Coronavirus Damages Lung Cells Within Mere Hours And What Drugs Could Halt COVID-19 Infection - SciTechDaily - February 1st, 2021
- Orchard Therapeutics Outlines Comprehensive Presence at 2021 WORLDSymposium - GlobeNewswire - February 1st, 2021
- NurOwn May Be Given to Early ALS Patients in US Who Finished Phase... - ALS News Today - December 20th, 2020
- Be Biopharma debuts with $52M to advance engineered B-cell therapies - FierceBiotech - October 24th, 2020
- Targeted Therapy for Non-Hodgkin Lymphoma: Current Progress and Future Plans - Cancer Therapy Advisor - September 5th, 2020
- Massachusetts Eye and Ear Enters Licensing Agreement with Biogen to Develop Treatment for Inherited Retinal Disorder - Newswise - July 2nd, 2020
- Startup targets glioblastoma tumors with CAR-T therapy - FierceBiotech - May 28th, 2020
- Infrared Laser Treatment of TBI, PTSD, and Depression: An Expert Perspective - Psychiatry Advisor - April 3rd, 2020
- 10 Of The Biggest World Revelations In The 21st Century - World Atlas - February 29th, 2020
- Where Are They Now? Top 3 Biotech Startups From NextGen Bio Class of 2018 - BioSpace - January 10th, 2020
- Firm adds a new wrinkle to anti-aging products - Williamson Daily News - January 5th, 2020
- Top Emerging Technologies of the Year - Technowize - December 29th, 2019
- New Podcast Sponsored by Asymmetrex Increases Awareness to the Need for Stem Cell Dose in Stem Cell Treatments - PR Web - November 9th, 2019
- Exercise found to block chronic inflammation in mice - Harvard Gazette - November 9th, 2019
- Arkuda bags $44M to target progranulin and head off inherited dementia - FierceBiotech - November 9th, 2019
- New study reveals why breast cancer spreads to the brain - USC News - October 23rd, 2019
- Comparison of Merus N.V. (MRUS) and Sage Therapeutics Inc. (NASDAQ:SAGE) - MS Wkly - October 23rd, 2019
- Reviewing Cellectis S.A. (CLLS)'s and Magenta Therapeutics Inc. (NASDAQ:MGTA)'s results - MS Wkly - October 23rd, 2019
- Massachusetts Stem Cells | Stem Cell TV - September 10th, 2019
- Chronic variable stress activates hematopoietic stem cells ... - April 12th, 2019
- Boston, MA, Stem Cell Transplant, Weston, Nantucket ... - January 10th, 2019
- Cloning/Embryonic Stem Cells - National Human Genome ... - July 5th, 2018
- Alternate Methods for Preparing Pluripotent Stem Cells ... - September 25th, 2017
- Doubts raised about CRISPR gene-editing study in human embryos - Nature.com - September 2nd, 2017
- For Lowell native, stem cell match becomes a match as friends - Lowell Sun - September 2nd, 2017
- Lymphoma Patient's Brain Tumor Disappeared After She Received JCAR017, Study Reports - Lymphoma News Today - September 2nd, 2017
- Asymmetrex Introduces New Contract Service For Producing ... - PR Web (press release) - August 29th, 2017
- ORGANOID - Science Magazine - August 27th, 2017
- Current humanized mice not good models for studying stem cell transplants, say researchers - Scope (blog) - August 27th, 2017
- Mouse Model of Human Immune System Inadequate for Stem Cell ... - Technology Networks - August 27th, 2017
- CRISPR fixes disease gene in viable human embryos - Nature.com - August 6th, 2017
- X4 joins hands with Yale on rare disease program - FierceBiotech - August 6th, 2017
- TGF-1: ALS Astrocytes' Secret Sauce? - ALS Research Forum - August 6th, 2017
- From Stem Cells to Human Development - September 2016 ... - December 4th, 2016
- Stem cell controversy - Wikipedia - December 1st, 2016
- What Are Stem Cells? - Massachusetts General Hospital ... - November 22nd, 2016
- New England Cord Blood Bank - Cord Blood and Cord Tissue ... - November 22nd, 2016
- Stem-cell-based therapy promising for treatment of breast ... - September 26th, 2016
- Stem Cell FAQ - Massachusetts General Hospital, Boston, MA - July 27th, 2016
- Stem Cell Facts - University of Massachusetts Medical School - July 27th, 2016
- Scientists engineer toxin-secreting stem cells to treat ... - October 19th, 2015
- Cloning/Embryonic Stem Cells - Genome.gov - October 19th, 2015
- Biomedical engineer developing nanomaterial for healing broken bones - March 18th, 2015
- Researchers identify a vital protein that can determine head and brain development - March 13th, 2015