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

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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