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

- - - - -

Risks of boosting NAD?

nad+;nad; nr; nmn; senescent cells

  • This topic is locked This topic is locked
2 replies to this topic

#1 Harkijn

  • Member
  • 705 posts
  • 202
  • Location:Amsterdam
  • NO

Posted 06 May 2019 - 02:12 PM

Just a heads up for those who only read the NAD threads:



  • Informative x 1
  • like x 1

#2 ledgf

  • Guest
  • 40 posts
  • 6
  • Location:New Hampshire

Posted 06 May 2019 - 06:11 PM

Improving mitochondrial health reduces cancer risk, it doesn't raise it. 

Cancer cells shut down the mitochondria and go anaerobic. 

  • Needs references x 1
  • Off-Topic x 1
  • Agree x 1

#3 smithx

  • Guest
  • 1,205 posts
  • 355

Posted 06 May 2019 - 09:33 PM


NAD+ metabolism governs the proinflammatory senescence-associated secretome


Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD+metabolism influences both tissue ageing and cancer. However, the role of NAD+ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ sal-vage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA–NAMPT–NAD+ signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD+ metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.





HMGA1 promotes senescence-associated growth arrest11. Here, we showed that HMGA1 plays an instrumental role in the proin-flammatory SASP by upregulating NAMPT through an enhancer element. Thus, HMGA1 couples the senescence-associated cell growth arrest and the proinflammatory SASP during senescence. Interestingly, HMGA1 is often upregulated in human cancers and its overexpression correlates with a poor prognosis in many can-cer types8,34. However, the tumour suppressive effects of HMGA proteins depend on the integrity of the senescence machinery, and HMGA proteins become oncogenic in cells that have bypassed senescence11. Thus, HMGA1 is no longer tumour suppressive in senescence-bypassed cancer cells. Our data show that inhibition of HMGA1 suppresses the SASP. This raises the possibility that tar-geting HMGA1-regulated NAMPT may be an effective approach to suppress a proinflammatory tumour microenvironment in HMGA1-overexpressing tumours. Indeed, NAMPT inhibitors are already in clinical trials. Thus, senescence-inducing cancer thera-peutics, including chemotherapy, may benefit from a combination with NAMPT inhibitors.Our results show that NAD+ metabolism plays a key role in determining the strength of the proinflammatory SASP. High SASP-associated senescence such as OIS is predominantly driven by a high NAD+/NADH ratio, while low SASP-associated senescence such as RS is primarily driven by DNA damage. This is consistent with the reported role of DNA damage in the SASP35. These dif-ferences in upstream signalling determined the strength of p38 MAPK and NF-κB signalling to ultimately dictate the strength of the SASP during different types of senescence. Indeed, increasing the NAD+/NADH ratio in RS by ectopic oncogenic RAS or NMN supplementation significantly enhanced the proinflammatory SASP. Notably, the proinflammatory SASP is tumorigenic36,37. Consistently, NMN supplementation promoted pancreatic ductal adenocarci-noma progression in a mouse model driven by oncogenic Kras. Thus, NAD+-augmenting dietary supplements may be tumori-genic in vivo in stressed conditions such as premalignant senescent lesions induced by activated oncogenes. However, it has been exten-sively documented that NMN supplements can alleviate certain age-related pathophysiological conditions, and NAD+-augmenting supplements, such as NMN, are currently in clinical development as nutraceuticals12. Thus, a dietary NAD+-augmenting supplement should be administered with precision to balance the advantageous anti-ageing effects with potential detrimental pro-tumorigenic side effects. In summary, our results show that NAD+ metabolism governs the proinflammatory SASP. Thus, our study will have far-reaching implications for understanding proinflammatory SASP regulation during senescence and precisely administering NAD+-augmenting anti-ageing dietary supplements such as NMN.



Edited by smithx, 06 May 2019 - 09:34 PM.

  • Informative x 3

0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users