Loss of epigenetic information as a cause of mammalian aging

Yang, Jae-Hyun; Hayano, Motoshi; Griffin, Patrick; Amorim, João A.; Bonkowski, Michael S.; Apostolides, John K.; Salfati, Elias; Blanchette, Marco; Munding, Elizabeth M.; Bhakta, Mital S.; Chew, Yap Ching; Guo, Wei; Yang, Xiaojing; Maybury-Lewis, Sun; Tian, Xiao; Ross, Jaime M.; Coppotelli, Giuseppe; Meer, Margarita; Rogers-Hammond, Ryan; Vera, Daniel; Lu, Yuancheng; Pippin, Jeffrey W.; Creswell, Michael; Dou, Zhixun; Xu, Caiyue; Mitchell, Sarah J.; Das, Abhirup; O’Connell, Brendan; Thakur, Sachin; Kane, Alice E.; Su, Qiao; Mohri, Yasuaki; Nishimura, Emi K.; Schaevitz, Laura; Garg, Neha; Balta, Ana-Maria; Rego, Meghan A.; Gregory-Ksander, Meredith; Jakobs, Tatjana C.; Zhong, Lei; Wakimoto, Hiroko; Andari, Jihad El; Grimm, Dirk; Mostoslavsky, Raúl; Wagers, Amy J.; Tsubota, Kazuo; Bonasera, Stephen J.; Palmeira, Carlos M.; Seidman, Jonathan G.; Seidman, Christine E.; Wolf, Norman S.; Kreiling, Jill A.; Sedivy, John M.; Murphy, Gëorge F.; Green, Edward; García, Benjamin A.; Berger, Shelley L.; Oberdoerffer, Philipp; Shankland, Stuart J.; Gladyshev, Vadim N.; Ksander, Bruce R.; Pfenning, Andreas R.; Rajman, Luis A.; Sinclair, David

doi:10.1016/j.cell.2022.12.027

Cited by 320 publications

(262 citation statements)

References 189 publications

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“…In the same way that Harvard researchers were recently able to advance cellular and organismal age forwards and backwards by the induction of just a few DNA breaks and then demonstrate their phenotypical rescue with the OSK Yamanaka stem cell factors [ 235 ] so too models of cannabis exposure lend themselves to similar exploration by experimental induction of aging in cells and model organisms and then their rescue either with a subset of the Yamanaka factors [ 184 , 185 , 186 , 187 , 188 , 235 ] or chemical cocktails [ 236 ], which are similarly directed. Thus, cannabinoid research could intersect powerfully with aging research in general at a time when the whole field is making important advances.…”

Section: Mechanisms Of Cannabinoid Genotoxicitymentioning

confidence: 99%

Clinical Epigenomic Explanation of the Epidemiology of Cannabinoid Genotoxicity Manifesting as Transgenerational Teratogenesis, Cancerogenesis and Aging Acceleration

Reece

Hulse

2023

IJERPH

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As global interest in the therapeutic potential of cannabis and its’ derivatives for the management of selected diseases increases, it is increasingly imperative that the toxic profile of cannabinoids be thoroughly understood in order to correctly assess the balance between the therapeutic risks and benefits. Modern studies across a number of jurisdictions, including Canada, Australia, the US and Europe have confirmed that some of the most worrying and severe historical reports of both congenital anomalies and cancer induction following cannabis exposure actually underestimate the multisystem thousand megabase-scale transgenerational genetic damage. These findings from teratogenic and carcinogenic literature are supported by recent data showing the accelerated patterns of chronic disease and the advanced DNA methylation epigenomic clock age in cannabis exposed patients. Together, the increased multisystem carcinogenesis, teratogenesis and accelerated aging point strongly to cannabinoid-related genotoxicity being much more clinically significant than it is widely supposed and, thus, of very considerable public health and multigenerational impact. Recently reported longitudinal epigenome-wide association studies elegantly explain many of these observed effects with considerable methodological sophistication, including multiple pathways for the inhibition of the normal chromosomal segregation and DNA repair, the inhibition of the basic epigenetic machinery for DNA methylation and the demethylation and telomerase acceleration of the epigenomic promoter hypermethylation characterizing aging. For cancer, 810 hits were also noted. The types of malignancy which were observed have all been documented epidemiologically. Detailed epigenomic explications of the brain, heart, face, uronephrological, gastrointestinal and limb development were provided, which amply explained the observed teratological patterns, including the inhibition of the key morphogenic gradients. Hence, these major epigenomic insights constituted a powerful new series of arguments which advanced both our understanding of the downstream sequalae of multisystem multigenerational cannabinoid genotoxicity and also, since mechanisms are key to the causal argument, inveighed strongly in favor of the causal nature of the relationship. In this introductory conceptual overview, we present the various aspects of this novel synthetic paradigmatic framework. Such concepts suggest and, indeed, indicate numerous fields for further investigation and basic science research to advance the exploration of many important issues in biology, clinical medicine and population health. Given this, it is imperative we correctly appraise the risk–benefit ratio for each potential cannabis application, considering the potency, severity of disease, stage of human development and duration of use.

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Section: Mechanisms Of Cannabinoid Genotoxicitymentioning

confidence: 99%

Clinical Epigenomic Explanation of the Epidemiology of Cannabinoid Genotoxicity Manifesting as Transgenerational Teratogenesis, Cancerogenesis and Aging Acceleration

Reece

Hulse

2023

IJERPH

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“…The concept of information in biology has a long history [ 28 ], and biological systems can be seen as highly complex information systems. Likewise, the idea that ageing could be linked to information decay or loss has been proposed, in particular in the context of the information theory of ageing [ 29 – 31 ]. According to this theory, loss of genetic [ 29 ] or epigenetic [ 30 , 31 ] information with age, driven by DNA damage, is the primary cause of ageing.…”

Section: Introductionmentioning

confidence: 99%

Ageing as a software design flaw

Magalhães

2023

Genome Biol

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Ageing is inherent to all human beings, yet why we age remains a hotly contested topic. Most mechanistic explanations of ageing posit that ageing is caused by the accumulation of one or more forms of molecular damage. Here, I propose that we age not because of inevitable damage to the hardware but rather because of intrinsic design flaws in the software, defined as the DNA code that orchestrates how a single cell develops into an adult organism. As the developmental software runs, its sequence of events is reflected in shifting cellular epigenetic states. Overall, I suggest that to understand ageing we need to decode our software and the flow of epigenetic information throughout the life course.

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“…Chemical modifications add to the diversity of biological macromolecules (e.g., DNA, RNA, and protein) and expand their molecular functions, and the aberrance of such modifications are found as one of the major causes of human diseases and aging (Flavahan et al, 2017;Cavalli and Heard, 2019;Yang et al, 2023). Due to the prominent roles of RNA modifications in human diseases such as cancer and the promise of targeting dysregulated RNA modification machineries in translational medicine (Huang et al, 2020a), the study of RNA modifications (e.g., m 6 A, m 1 A, m 5 C, m 6 Am, pseudouridine, and A-to-I editing) represents the new Frontier in the epigenetics field.…”

Section: Introductionmentioning

confidence: 99%