• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo

A human tissue‐specific transcriptomic analysis reveals a complex relationship between aging, cancer, and cellular sen..

cell division geriatric oncology oncogenesis transcriptome tumor

  • Please log in to reply
6 replies to this topic
⌛⇒ new years donation: support LE labs

#1 Engadin

  • Guest
  • 127 posts
  • 286
  • Location:Madrid
  • NO

Posted 27 September 2019 - 06:35 PM


.

 

 

 

A human tissue‐specific transcriptomic analysis reveals a complex relationship between aging, cancer, and cellular senescence.

 

 

 

 

S O U R C E :   Aging Cell

 

 

 

 

 

Abstract

 

Aging is the biggest risk factor for cancer, but the mechanisms linking these two processes remain unclear. Using GTEx and TCGA data, we compared genes differentially expressed with age and genes differentially expressed in cancer among nine human tissues. In most tissues, aging and cancer gene expression pattern changed in the opposite direction. The exception was thyroid and uterus, where we found transcriptomic changes in the same direction in aging and in their corresponding cancers. The overlapping sets between genes differentially expressed with age and genes differentially expressed in cancer across tissues were enriched for several processes, mainly cell cycle and the immune system. Moreover, cellular senescence signatures, derived from a meta‐analysis, changed in the same direction as aging in human tissues and in the opposite direction of cancer signatures. Therefore, transcriptomic changes in aging and in cellular senescence might relate to a decrease in cell proliferation, while cancer transcriptomic changes shift toward enhanced cell division. Our results highlight the complex relationship between aging and cancer and suggest that, while in general aging processes might be opposite to cancer, the transcriptomic links between human aging and cancer are tissue‐specific.

 

 

Aging is the biggest risk factor for cancer (de Magalhaes, 2013). However, the biological mechanisms behind this link are still unclear. Gene expression analyses have been used to study cancer (Cieslik & Chinnaiyan, 2018) and aging (de Magalhaes, Curado, & Church, 2009; Yang et al., 2015), but only a few studies have investigated the relationship between gene expression changes in these two processes (Aramillo Irizar et al., 2018). In particular, comparisons between human tissue‐specific genes differentially expressed with age (age‐DEGs) and genes differentially expressed in cancer (cancer‐DEGs) are lacking. Cellular senescence is a state of irreversible cell cycle arrest and has been regarded as an anti‐tumor mechanism (Campisi, 2013). However, accumulating evidence has suggested that senescent cells could also promote cancer (Demaria et al., 2017). Many studies have attempted to identify gene expression signatures of senescence (Kim et al., 2013), but comparisons between cellular senescence signatures, age‐DEGs, and cancer‐DEGs are also lacking.

 

The Genotype‐Tissue Expression (GTEx) Project has profiled gene expression from noncancerous tissues of nearly 1,000 individuals (age 20–79 years) over 53 sampled sites (Ardlie et al., 2015). The Cancer Genome Atlas (TCGA) has sequenced tumor samples from more than 10,000 patients covering 33 cancer types (Ding et al., 2018). Here, we investigated the relationship between transcriptomic changes in aged human tissue and their corresponding cancer by analyzing gene expression data from GTEx and TCGA. In addition, we conducted a meta‐analysis using publicly available datasets to identify cellular senescence signature genes and compared them with age‐DEGs and cancer‐DEGs.

 

We first identified age‐DEGs in 26 tissues from GTEx (v7), nine tissues (breast, colon, esophagus, liver, lung, prostate, stomach, thyroid, and uterus) were selected for subsequent analyses (Table S1). The numbers of significant age‐DEGs (p‐value with Benjamini–Hochberg correction < .05 and absolute fold change > 1.5; moderated t test) varied between different tissues (Figure 1a, Figure S1, Data S1). We identified cancer‐DEGs by analyzing nine TCGA datasets for which the tissues of origin were matched to the GTEx tissues used in this study (Table S1, Figure S2). The numbers of cancer‐DEGs (p‐value with Benjamini–Hochberg correction < .01 and absolute fold change > 2; moderated t test) are shown in Figure 1b (Data S2).

 

 

acel13041-fig-0001-m.jpg

 

Figure 1.

The relationship between age‐DEGs and cancer‐DEGs. (a) Number of age‐DEGs. (b) Number of cancer‐DEGs. The full study name of TCGA projects can be found in the Table S1. © Fold change with age in GTEx data of cancer‐DEGs. Numbers indicate p‐values. (d) Overlap between age‐DEGs and cancer‐DEGs. Numbers represent p‐values with Benjamini–Hochberg correction. N.S. denotes nonsignificant overlap. Colors correspond to odds ratio. (e) GO enrichment analysis of significantly overlapping gene sets. The plot shows examples of significant enriched terms (p‐value with Benjamini–Hochberg correction < .1)

 

 

After obtaining a list of cancer‐DEGs, we examined the fold change with age in GTEx tissues of the cancer‐DEGs. We observed a significantly (p‐value < .05; Mann–Whitney U test) higher fold change with age in genes down‐regulated with cancer when compared to genes up‐regulated with cancer for most cancer types, with the opposite being observed in two tissues: THCA‐thyroid and UCEC‐uterus (Figure 1c). We overlapped age‐DEGs and cancer‐DEGs for each tissue. Consistent with the result in Figure 1c, genes changing in the opposite direction between aging and cancer significantly overlapped more often than genes changing in the same direction in breast, colon, esophagus, lung, and prostate (Fisher's exact test, Benjamini–Hochberg correction) (Figure 1d). For thyroid, the overlap was significant for genes changing in the same direction. There was no significant overlap in liver and stomach, which might be explained by the small number of age‐DEGs in these tissues. In uterus, however, the overlap was significant in all cases. The same analyses were also performed for the brain and glioblastoma multiforme (GBM), where we found the same direction of transcriptomic changes between aging and cancer. However, due to the small number of control brain samples (five samples) in TCGA and because they lack information of the patient age, we decided to include the brain result only in the (Figure S3, Data S3).

 

We performed GO enrichment analysis and found that 6 out of 20 significantly overlapping sets were enriched in GO terms (Figure 1e, Data S3). Genes down‐regulated with age—up‐regulated in cancer, in colon, and lung, were related to cell cycle. Cell cycle terms were also enriched in genes up‐regulated with age—up‐regulated in cancer in the uterus. Uncontrolled cell proliferation in the aging uterus often leads to endothelial hyperplasia and could lead to endometrial cancer (Damle et al., 2013). Immune‐related terms were enriched in genes down‐regulated with age—down‐regulated in cancer in the colon. The immune system plays an important role in preventing cancer through immunosurveillance (Ribatti, 2017). Compromised immune function with age could provide an immunosuppressive microenvironment, allowing cancer cells to evade immunosurveillance (Fulop et al., 2010).

 

Our results highlight the tissue‐specific nature of transcriptomic changes in human aging and cancer, even though in general they changed in the opposite direction for most tissues, in line with another study (Aramillo Irizar et al., 2018). One possible interpretation is that molecular changes during aging processes may oppose cancer development. Another potential interpretation for our results, from an evolutionary perspective, is that aging‐related changes in tissue microenvironment, leading to the decrease in tissue robustness, might provide a selective advantage for cells harboring oncogenic mutations (Henry, Marusyk, Zaberezhnyy, Adane, & DeGregori, 2010; Parikh, Shuck, Gagea, Shen, & Donehower, 2018). We note that the incidences of thyroid and uterine cancer are different from others, they plateau at an younger age than other cancers (de Magalhaes, 2013). Interestingly, these are the organs in which we found the same direction of transcriptomic changes between aging and cancer. One limitation of our work is that we are unable to distinguish changes in transcriptome during aging within each cell type in the tissue or changes in tissue cell composition.

 

 

 

 

.../...

 

 

 

 

F O R   T H E   R E S T   O F   T H E   S T U D Y,   P L E A S E   V I S I T   T H E   S O U R C E .

 

 

 

 

.


Edited by Engadin, 27 September 2019 - 06:36 PM.

  • Informative x 1

#2 sedentary

  • Guest
  • 112 posts
  • 6
  • Location:Charlestown

Posted 27 September 2019 - 09:19 PM

interesting article about senescent cells; https://medicalxpres...ers-cancer.html

 

"One of the reasons our bodies have evolved to have senescent cells is to suppress cancers. But then it seems that senescent cells accumulate in aged human tissues and may contribute to ageing and degeneration. Importantly, our work challenges the traditional view concerning the relationship between cancer and ageing and suggests that ageing processes may hinder cancer development."

 

not to be off topic but its about fisetin being a senolytic and this article is related i believe. if not transfer it to a separate topic, thanks.


  • Informative x 1

Click HERE to rent this BIOSCIENCE adspot to support LongeCity (this will replace the google ad above).

#3 MikeDC

  • Guest
  • 1,386 posts
  • -461
  • Location:Virginia

Posted 28 September 2019 - 12:30 AM

interesting article about senescent cells; https://medicalxpres...ers-cancer.html

"One of the reasons our bodies have evolved to have senescent cells is to suppress cancers. But then it seems that senescent cells accumulate in aged human tissues and may contribute to ageing and degeneration. Importantly, our work challenges the traditional view concerning the relationship between cancer and ageing and suggests that ageing processes may hinder cancer development."

not to be off topic but its about fisetin being a senolytic and this article is related i believe. if not transfer it to a separate topic, thanks.

New study shows increasing NAD+ reduces senescent cell accumulation.
https://www.ncbi.nlm.../?i=3&from=cd38
  • Informative x 1

⌛⇒ new years donation: support LE labs

#4 sedentary

  • Guest
  • 112 posts
  • 6
  • Location:Charlestown

Posted 28 September 2019 - 02:28 AM

from what i read reducing cell senescents might not be a good idea.did you read same article?



#5 Harkijn

  • Member
  • 670 posts
  • 190
  • Location:Amsterdam
  • NO

Posted 28 September 2019 - 06:03 AM

from what i read reducing cell senescents might not be a good idea.did you read same article?

Cell senescence is for the most part a perfectly healthy process. However once they have survived their purpose they turn dysfunctional and start to send out SASP. The ideal senolytic culls selectively the dysfunctional ones.


  • Needs references x 1

#6 MikeDC

  • Guest
  • 1,386 posts
  • -461
  • Location:Virginia

Posted 28 September 2019 - 08:39 PM

Cell senescence is for the most part a perfectly healthy process. However once they have survived their purpose they turn dysfunctional and start to send out SASP. The ideal senolytic culls selectively the dysfunctional ones.


Cell senescence is normal. But accumulation of senescent cells is not. In perfect conditions, senescent cells just die. I read a study somewhere that says senescent cells generally have DNA breaks than prevent apoptosis. Keep healthy levels of NAD+ will reduce DNA damage and senescent cells accumulation.

Click HERE to rent this BIOSCIENCE adspot to support LongeCity (this will replace the google ad above).

#7 OP2040

  • Guest
  • 491 posts
  • 91
  • Location:United States
  • NO

Posted 30 September 2019 - 03:10 PM

I think we almost need to change our language to express things correctly in biology.  Biological systems are processes.  As such, and as we've discovered, processes can be good, bad or neutral depending on time and context.  So when we say senescent cells are bad, or they are good for inhibiting cancer, the frustratingly correct answer is always "i depends".  

 

Lets talk about cellular senescence as a cyclical homeostatic process.   It seems to me, it goes something like this in a healthy body:

DNA damage > Damage repair failure > Cellular damage > Cellular senescence > Immune clearance

 

So which one of these changes with age?  Studies show that the rate of dna damage stays surprisingly stable over a lifetime.  However, dna repair falls, cellular damage/senescence rise, and finally immune clearance falls.

 

What we are trying to do is basically engineer a replacement for the last step in the process.  That is absolutely a huge piece of the puzzle and we should definitely pursue it.  But given the process, it will not effect the most critical aging change in the process, that is the failure of dna repair pathways.  For the sake of argument, lets assume that Sirtuins are a good proxy for upregulating this pathway back to youthful levels.  

 

If all of the above is true, then we should definitely continue to use Sirtuins upregulation, or any other dna repair intervention, alongside senolytics.  Senolytics are going to have a huge impact on healthspan and burden of disease.  But holding back on dna repair, as some people are suggesting, just means that tissues will become exhausted at the same rate, or possible faster.

 

The other question usually asked is whether we should intervene in these things at the same time.  I cycle them like everyone else.  But if we're trying to engineer a youthful process, we would never take breaks in dna repair since it is such a fundamental part of longevity.  Most studies on long-lived animals support this notion.

 

As for the big C, restoring immunity will be the best near-term solution.  Until then, we are all rolling the dice.  But I like anyone's chances with higher dna repair and engineered senescent cell clearance, than with either one alone or none.


  • Well Written x 1
  • like x 1





Also tagged with one or more of these keywords: cell division, geriatric oncology, oncogenesis, transcriptome, tumor

0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users