Diet has strong effects on aging and diseases such as cancer
Over-eatingCalorie Restriction (CR)
How does diet regulate organ regeneration and cancer?
Organism) Lifespan)increase)with)caloric)restric4on)(CR))Yeast& 3(fold&Worms& 2(3&fold&Flies& 2(fold&Mice& 30(50%&Monkeys& 10%&or&no&effect&Humans) Not)studied)
Fontana L et al. Science. 2010 Apr 16;328(5976):321-6 Mattison, J. A. et al. Nature 489, 318–321 (2012) Coleman RJ et al. Nat Commun. 2014 Apr 1;5:3557
Extending life span with caloric restriction - from yeast to humans
Lgr5+ stem cells at the base of crypts maintain the intestinal epithelium
Clevers,Nature2007;Lewis,NatureReviewsGene2cs2006
Lgr5+
Lgr5‐Lgr5‐
Lgr5‐Lgr5‐
GFPhi
GFPlow
Lgr5+
stem cell
Paneth cell
niche
T Sato et al. Nature 000, 1-4 (2009) doi:10.1038/nature07935
Single Lgr5+ cells generate crypt–villus structures.
Sato et al 2009 Yilmaz et al 2012
Engineering “mini-intestines” in culture
Test effects of dietary components in 3-D miniature organs
cADPR
Calorie restriction
mTORC1
differentiation
self-renewal
Effect of a low calorie state on stem cells
Can CR or its mimetics enhance intestinal regeneration in patients?
Smoking
Overweight and obesity
Lack of exercise
Diet
Occupation
Viruses
Family history
Alcohol
UV and ionizing radiation
Prescription Drugs
Reproductive factors
Pollution
adapted from Colditz et al., Science Translation Medicine, 2012
Smoking
Overweight and obesity
Obesity is a diet-modifiable cause of cancer
HFD boosts stem cell function
Control
HFD
**
*
*
**
*
0
0.2
0.4
0.6
0.8
Control' HFD'
Org
anoi
d pe
r cry
pt
'
*
PAVehicle
organoids from crypts
Vehicle PA
2
1
0
3
4 *%
GFP
hi p
ositi
ve s
tem
cel
ls
Org
anoi
d pe
r ste
m c
ell
Vehicle PA
Vehicle
PA
Side
Sca
tter A
rea
EGFP
1.5 ± 0.3%
3.3 ± 0.7%**0
0.06
0.04
0.02
0.10
0.08
**0.12
Ex vivo exposure of “mini-intestines” to Palmitic Acid boosts stem cell numbers and function
Similar results observed with oleic acid and other lipids
If stem cell activity increases, HFD should raise tumor incidence
Inci
denc
e
0.8
0.6
0.4
0.2
0.7
0.5
0.3
0.1
Number of intestinal carcinoma per mouse
Aged Aged+HFD