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Optical Acceleration and Ions and Perspective for Biomedicine.Bologna, November 4-5, 2011
AGING AND RADIATION: A CRITICAL UPDATE CLAUDIO FRANCESCHI
Department of Experimental Pathology Centro Interdipartimentale “Luigi Galvani” per la Bioinformatica e la Biocomplessità
University of Bologna, Italy
C:\Programmi\Qualcomm\Eudora\attach\angi_bio_110309_4451.jpg
Funding agencies
EU PROJECTS • GEHA (genetics) 2004-2010, coordinator • PROTEOMAGE (proteomics) 2006-2011 • MARKAGE (biomarkers) 2008-2012 • MYOAGE (muscle) 2009-2012 • RISTOMED (nutrition) 2009-2011 • IDEAL (late effects of early events) 2011-2016 • NU-AGE (nutrition) 2011-2016, coordinator
Italian Ministry of University, Italian Ministry of Health, local
foundations (CARISBO, Fondazione del Monte), Italian Ministry of Health, Emilia-Romagna Region, UNIBO
The centenarians (100+)
At present (January 1st, 2011) in Italy there is a total of 16,145 centenarians
over a population of 60,626,422 inhabitants, i.e. 1 centenarian over 3,755 persons
The women longevity paradox
There are:
13,040 100+ women
3,105 100+ men
ratio 5.2
Despite their lower death rate at all ages, women have higher overall rates of physical illness, more disability days, more doctor’s visits and hospital stays than men
Aging is a complex trait
The mosaic of aging great variability at all levels of biological organization: - macromolecules - organelles - cells - organs - individuals - populations
Cevenini et al.,
Theoretical / Methodological
Considerations
How to approach complex biological traits?
Major concepts for complex biological
traits / systems
• Degeneracy (Redundancy)
• Network – Robustness - Frailty
• Bow-tie (Homeostasis)
Aging
is a complex trait:
the phenotype of centenarians
The remodelling theory of aging (Franceschi 1995, 2000)
The phenotype of aged subjects
results from the capability of the body
of responding/adapting
to the accumulation of
unrepaired macromolecular damages
and their signalling capability
REMODELLING increasing robustness
Mortality decelerates
at advanced ages
A new phase of life ?
Inspired by Gavrilov and Gavrilova
Gompertz curve semilog plot
100+ are likely
robust since
the beginning
but they
became even
more robust
with aging
Aging and
Antagonistic Pleiotropy
REMODELLING is based on and performed by
fundamental biological responses,
such as DNA repair, apoptosis,
immune response / inflammation,
ALL POSITIVE FOR
SURVIVAL until REPRODUCTION
Such responses may turn detrimental
in the post-reproductive period of life,
largely unpredicted by evolution
The ROBUSTNESS
of a Complex System
cannot be infinite and fully pervasive
Somewhere in the system there is always a hidden FRAILTY
dictated by evolution
In Complex Systems
Robustness and Frailty
occur concomitantly
The phenotype of
centenarians
is unexpectedly complex
being a mixture of
robustness and frailty
Centenarians DO HAVE genetic risk alleles
for major age-related diseases despite their
remarkable postponing / avoiding them
0
50
100
150
200
250
0
10
20 Giovani
Centenari
ACTH CRF Cortisol
*
ng/m
l
* * YOUNG
CENTENARIANS
Monti et al., Neuroimmunomodulation 2008
Centenarians are stressed !
Passeri et al. J Clin Endocrinol Metab 2003, 88:5109-15
inflammatory markers (IL-6)
are elevated in centenarians
Age (years)
IR (
HO
MA
)
1
2
3
4
5
6
20-40 40-50 50-60 60-70 70-80 80-90 90-100 >100
p for trend < 0.01
LACK OF INSULIN RESISTANCE
IN CENTENARIANS
Paolisso et al., Exp. Gerontol., 37:149-156,2001
IGF-1 plasma levels are low in centenarians
protecting from cancer but favoring sarcopenia (antagonistic pleiotropy trade off)
Bonafè et al., J Clin Endocrinol Metab 2003
The IGF-1/insulin
pathway of
centenarians is
remarkably
similar to that of
long living animal
models
Centenarians, n=156 Centenarians
Offspring, n=267
Offspring of non long-
lived parents, n=107
Age (mean) yrs (min-max) 100.8 (98-111) 70.2 (54-88) 71.1 (50-86)
Male, n (%) 34 (21.8) 109 (40.8) 56 (52.3)
Female, n (%) 122 (78.2) 158 (59.2) 51 (47.7)
Education, yrs, mean (SD) 6.7 (4.7) 11.1 (5.3) 10.1 (4.3)
Centenarian Study 2009 (PRIN with Daniela Mari, Giovanni Vitale, Paolo Sansoni and Calogero Caruso)
IGF1 plasma levels and bioactivity are low not only in centenarians but also in their offspring, suggesting a genetic control of
this parameter
IGF1, IL-6 and sarcopenia
In 526 subjects of different ages (20-102 years of
age), high plasma levels of IL-6 were associated
with loss of muscle strength and power while
higher levels of IGF-1 were protective
During the aging process
Robustness and Frailty
occur concomitantly
0 100
R F
C
AGE 70
Remodelling accumulation of Robustness (R) +
accumulation of Frailty (F) +
loss of Complexity (C)
individual variability
(genetically determined)
INFLAMMAGING
and the consequent change of
body microenvironment
is a major example of the
concomitant accumulation
of robustness and frailty
In Aging
Robustness and Frailty
occurs concomitantly
The inflammatory theory
of Aging
Ann. N.Y. Acad. Sci., 908, 244-254, 2000
Ann. N.Y. Acad. Sci., 908, 244-254, 2000
De Martinis et al., FEBS Lett. 579, 2035-9, 2005
I
N
F
L
A
M
M
A
G
I
N
G
Obesity
Metabolic syndrome
Type 2 Diabetes
Cardiovascular
diseases Cancer
Alzheimer
dementia
Sarcopenia
Frailty
Depression
INFLAMMATION
The Diseasome of Inflamm-aging
Inspired by Pedersen, 2010
Inflammaging and Cancer breast cancer as an example
The multishell
cytokine network
model
Bonafè, Storci & Franceschi, BioEssays, in press
BioEssays 2012, in press
Epigenetic changes
STRESSORS
Epigenetic re-programming
of the aging process is apparently possible
and should be pursued
Epigenetic changes/
reprogramming
Aging
Epigenetic changes of DNA (e.g. methylation) modulate the function of DNA (switch on and off of genes) and create new
phenotypes WITHOUT CHANGING THE DNA SEQUENCE
MODEL (all females) 25 Centenarians
(>100 yrs old)
25 Centenarian’s Offspring (CO) (with one parent centenarian and the other also long lived)
25 Offspring of Non Long-Lived Parents (NLLO)
(subjects with both parents non long-lived, died at an age lower than the life expectancy for the cohort)
25 Young subjects (20-30 years old)
THE CENTENARIAN EPIGENOME CIG, University of Bologna and Centro Auxologico Italiano, Cusano Milanino, Mi, Italy.
Paper submitted
In collaboration with Daniela Mari, Giovanni Vitale, Annamaria Diblasio, Laura Bucci, Rita Ostan,
Daniela Monti
DNA SAMPLES
BISULFITE Conversion
Whole GENOME Amplification
HYBRIDIZATION
STAINING
MEASUREMENT
27,578 CpG 20,006 CODING REGIONS
7,572 REPETITIVE DNA
PLATFORM:
Illumina Human Methylation 27 BeadChips
Illumina 27K > 27,000 CpG spanning 14,495 genes
(PROMOTERS) CpG localised in CpG island CpG with a functional role (20,006 CpG sites) CpG repeats outside of islands CpG with an undefined role (7,572 CpG sites)
Genome wide methylation profiling
Methylation of Alu-enriched sequences
Methylation value of CpG islands
INFLAMM-AGING
Gut microbiota
+
Invisible Partners bacteria in the different body sites
GM bacterial biodiversity
• 10 to 100 trillion • 1,800 genera • 16,000 phylotypes • their collective genome (microbiome) contains 3.3 million non-redundant
microbial genes, ~ 150 times the genes of the human genome
Each human has a “metagenome” (human genome + microbiome) and has to be considered a “superorganism”
• Firmicutes 65% • Bacteroidetes 25% • Proteobacteria 8% • Actinobacteria 5% • Fusobacteria 1%
Each individual carries about half a million prevalent microbial genes
Gut Microbiota & Metabolomics
In collaboration with Patrizia Brigidi, Marco Candela & Elena Biagi
University of Bologna Willem de Vos, University of Wageningen
Serge Rezzi & Sebastiano Collino, Nestec,Lausanne
Clustering of the HITChip phylogenetic GM fingerprints of Centenarians C, in green, Old Subjects K, blue
Young Y, orange.
15 centenarians out of 21
Biagi et al., 2010
RDA shows that 8.9% of the total variability of the GM can be related to the pattern of pro-inflammatory cytokines
P < 0.01 according to
MCPP Monte Carlo Permutation
Procedure
Biagi et al., 2010
Urine metabolome and faeces microbiome
p. 49 Name and Department Click View --> Header and Footer to modify yyyy-mm-dd
• Spearman correlation between Bacterial counts at Level 1 and 1H NMR spectra
• Correlation values filtered according to P value [not significant P’s are considered
with R=0]. -P are not corrected for multiplicity testing -.
p. 50 Name and Department Click View --> Header and Footer to modify yyyy-mm-dd
Spearman correlation between Bacterial counts at Level 1 and 1H NMR spectra
INFLAMM-AGING
Gut microbiota
DIET
+
-
COOPERATION THEME 2: Food, Agriculture and Fisheries, and Biotechnology FP7-
KBBE-2010-4 Proposal full title: New dietary strategies addressing the specific needs of the elderly population for healthy ageing in Europe Proposal Acronym: NU-AGE Coordinator: Prof. Claudio Franceschi Funding scheme: Collaborative Project (large integrating project) 9M € Topic addressed: KBBE-2010-2-2-02: Diet and prevention of functional decline of the elderly
NU-AGE and Inflamm-aging
BASIC HYPOTHESIS & RATIONALE
Appropriate WHOLE DIET (an ad hoc fortified “mediterranean diet”) can decrease the level of the chronic, sub-clinical, low grade inflammatory process characteristic of old age we have proposed to call INFLAMM-AGING (Franceschi et al., 2000)
Franceschi et al., MAD 2007
Plasmatic mtDNA
Gut microbiome
? LONGEVITY
and
the balance between
pro- and anti
inflammatory stimuli
INFLAMM-AGING in a global perspective
• More attention should be paid to the relationship (at the epidemiological, cellular and molecular level) between and among apparently “different” diseases (CVD, T2D, dementia, obesity…) which eventually are likely much more overlapped (pathogenically) than previously thought
INFLAMM-AGING in a global perspective
• More attention should be paid to the relationship between systems biology/medicine and the social, economic, cultural/anthropological and political environment (levels/differences)
• More attention to population specificities
(population genetics, population immunology…)
The DISEASOME and network/systems medicine
AGING
CVD
Inspired by Barabasi, 2007
Obesity systems map courtesy of SJ Ulijaszek
