Cell division rates decrease with age, providing a potential explanation for the age-dependent deceleration in cancer incidence

Tomasetti, Cristian; Poling, Justin; Roberts, Nicholas J.; London, Nyall R.; Pittman, Meredith E.; Haffner, Michael C.; Rizzo, Anthony; Baras, Alex; Karim, Baktiar O.; Kim, Antônio; Heaphy, Christopher M.; Meeker, Alan K.; Hruban, Ralph H.; Iacobuzio‐Donahue, Christine A.; Vogelstein, Bert

doi:10.1073/pnas.1905722116

Cited by 67 publications

(62 citation statements)

References 39 publications

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“…of cancer cells. Recent in vivo work shows the cell division rate in stem cells declines with age(Tomasetti et al 2019), and we validate these findings mathematically, for the first time in cancer cells, showing the rate of proliferative decline is not uniform across all melanoma subtypes. Our framework can be used to test if the age-driven decline in cell division varies depending on the tissue of origin, and whether the lineage-specific cell division decline mirrors a decrease in cancer incidence observed in the very elderly population.…”

supporting

confidence: 71%

Biological sex and age shape melanoma tumour evolution

Lotz

Virós

2019

Preprint

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Many cancer types display sex and age disparity in incidence and outcome.Here, we establish a mathematical approach using cancer mutational data to analyze how sex and age shape the tumour genome. We model how agerelated (clock-like) somatic mutations that arise during cell division, and extrinsic (environmental) mutations accumulate in cancer genomes. As a proof-of-concept, we apply our approach to melanoma, a cancer driven by cell-intrinsic age-related mutations and extrinsic ultraviolet light-induced mutations, and show these mutation types differ in magnitude, chronology and by sex in the distinct molecular melanoma subtypes.Our model confirms age and sex are determinants of cellular mutation rate, shaping the final mutation composition. We show mathematically for the first time how, similar to non-cancer tissues, melanoma genomes reflect a decline in cell division during ageing. We find clock-like mutations strongly correlate with the acquisition of ultraviolet light-induced mutations, but critically, males present a higher number and rate of cell division-linked mutations. These data indicate the contribution of environmental damage to melanoma likely extends beyond genetic damage to affect cell division.

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supporting

confidence: 71%

Biological sex and age shape melanoma tumour evolution

Lotz

Virós

2019

Preprint

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“…In our previous research, we showed the fundamental role played by the number of cells, and the number of cell divisions, in determining cancer risk 15,[23][24][25] . A natural question is then to ask whether obesity has an effect on the size of our organs, and therefore on their total numbers of cells.…”

mentioning

confidence: 99%

“…And harmful inherited mutations appear to explain only a very small percentage (<5%) of obesity 7 . This is somewhat surprising since cancer is by and large the result of deleterious genetic and epigenetic changes as described by the somatic mutation theory of cancer [8][9][10] and successively solidified by genome-wide analyses [11][12][13][14][15][16] . How can obesity increase the risk of cancer if it does not increase a cell's mutational load?…”

mentioning

confidence: 99%

Larger organ size caused by obesity is a mechanism for higher cancer risk

Grant

Zhang

et al. 2020

Preprint

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Obesity increases significantly cancer risk in various organs. Although this has been recognized for decades, the mechanism through which this happens has never been explained. Here, we show that obese people (BMI ≥30) have on average 55% (95%CI: 46%-66%), 68% (95%CI: 59%-76%), and 39% (95%CI: 29%-49%) larger kidneys, liver, and pancreas, respectively. We also find a significant linear relationship between the increase in organ volume and the increase in cancer risk (P-value<10−12). These results provide a mechanism explaining why obese individuals have higher cancer risk in several organs: the larger the organ volume the more cells at risk of becoming cancerous. These findings are important for a better understanding of the effects that obesity has on cancer risk and, more generally, for the development of better preventive strategies to limit the mortality caused by obesity.

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“…As the body ages, the innate immune system gradually declines, a phenomenon now termed immunosenescence [145], resulting in decreased effector immune cell function; and healthy tissue renewal rate decreases dramatically [146]. As a result, the aged tissue microenvironment accumulates senescent cells, such as SASP-associated fibroblasts, and gains the infiltration of immune infiltrates such as immunosuppressive myeloid-derived suppressor cells (MDSCs) and T regulatory cells.…”

Section: The Ageing Immune System and Immunosenescencementioning

confidence: 99%

Senescent cells and macrophages: key players for regeneration?

Elder

Emmerson

2020

Open Biol.

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Over the last decade, our understanding of the physiological role of senescent cells has drastically evolved, from merely indicators of cellular stress and ageing to having a central role in regeneration and repair. Increasingly, studies have identified senescent cells and the senescence-associated secretory phenotype (SASP) as being critical in the regenerative process following injury; however, the timing and context at which the senescence programme is activated can lead to distinct outcomes. For example, a transient induction of senescent cells followed by rapid clearance at the early stages following injury promotes repair, while the long-term accumulation of senescent cells impairs tissue function and can lead to organ failure. A key role of the SASP is the recruitment of immune cells to the site of injury and the subsequent elimination of senescent cells. Among these cell types are macrophages, which have well-documented regulatory roles in all stages of regeneration and repair. However, while the role of senescent cells and macrophages in this process is starting to be explored, the specific interactions between these cell types and how these are important in the different stages of injury/reparative response still require further investigation. In this review, we consider the current literature regarding the interaction of these cell types, how their cooperation is important for regeneration and repair, and what questions remain to be answered to advance the field.

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Cell division rates decrease with age, providing a potential explanation for the age-dependent deceleration in cancer incidence

Cited by 67 publications

References 39 publications

Biological sex and age shape melanoma tumour evolution

Biological sex and age shape melanoma tumour evolution

Larger organ size caused by obesity is a mechanism for higher cancer risk

Senescent cells and macrophages: key players for regeneration?

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