the unique microenvironment of the aging human adult … 3. des... · the unique microenvironment...
TRANSCRIPT
Desmond J. Tobin
Centre for Skin Sciences,
University of Bradford, Great Britain
The unique microenvironment of the aging human adult scalp
Anti-ageing Skin care Conference,
Royal College of Physicians
London 7-8 June 2016 1/31
Humans: so-called ‘Naked’ Ape
Why are we so different? ‘Terminal Decline’ - evolution appears to have transformed terminal to vellus HF for more & better sweat glands.
Sweating advantage of having vellus >> terminal hair - greater evaporation potential (Nina Jablonski)
Human dense scalp terminal hair – an anomaly in mammal hair growth?
Human communication focused on head & face – body sites with potential for dramatic and luxuriant hair growth variations.
2/31
Life Stories of the Human Hair Follicle
Phase change in: calibre, length, colour
Lanugo Vellus Terminal
‘Vellus
-like’
‘Turbo-terminal’ 3/31
4/14
Corneocyte layers: Genital skin (6 ± 2),
face (9 ± 2), neck (10 ± 2), scalp (12 ± 2),
trunk (13 ± 4), & extremities (15 ± 4),
Soles/ palms (> 50)
4/31
Is human scalp different across ethnicities?
HF density variable between ethnicities:
Highest in Caucasian blonds,
Lowest in Mongoloid Asians (& Red-haired Caucasians).
5/31
How is human scalp different from other skin?
Scalp barrier function: Scrotum (x43); Forehead (6x); Scalp
/Axilla (3.55x). (hydrocortisone volar arm = 1). HF important.
Scalp prone to dryness, redness, dandruff, itchiness, inflam etc.
Vasculature: Carries more blood - head wounds bleed profusely
Adnexa: Sebaceous & sweat-glands. Sebum protect hair & scalp.
Sweat - cools, acidifies, etc.
Oil: Can clog HFs; dandruff linked
to bacteria that metabolizes oil to
produce fatty acids that cause itching
/swelling. cell turnover to produce
flakes trapped in hair.
“Bacteria had a stronger relationship with the severity of dandruff than fungi.
…adjusting balance of the bacteria on the scalp, by enhancing Propionibacterium
and suppressing Staphylococcus, might be a potential solution to lessen dandruff”.
(Xu et al, 2016)
6/31
Children: Epidermis thin with low Ki67-positive cells.
Low proportional % thickness of involucrin-positive layer.
19-21ys: Highest cell turnover & maximal epidermis
thickness.
>21yrs: keratinocyte proliferative activity.
Involucrin-positive layer: Absolute thickness constant at
different ages, but proportion in total epidermal thickness .
(Nozdrin et al, 2011)
Scalp Intrerfollicular Epidermis change with Age
7/31
Chronologic age - a HF sculptor
(adapted from A Schwan-Jonczyk, 2009)
Young adult Child
Late teens/early adulthood. hair caliber, cross-sectional irregularity, variation (caliber/ellipticities) - results in ‘fuller’ hair.
60s 70-80s
Old-Age: diameter & medulla, symmetrical fibers - smoother hair.
40-50 year old
Mid-Age: hair medulla & asymmetrical fibers - stiffer, less elastic, duller.
M
8/31
Impact of Extending Life expectancy & Life Span
~2-3yr 60 yr >100yr
Maximum lifespan
in mammals Jeanne
Calment
122y
Male AGA: 50% by 50y; ~70% later
Female AGA: 6% <50y; ~40% >70y
9/31
Non-scaring hair loss: 3 types (Whiting). Pattern, Diffuse & ‘Senescent’
Prototypical Human HF ‘aging’ - Genetic hair loss
Miniaturization & asymmetric loss of thicker hairs? (Mirmirani et al, 2010)
Terminal Hair
Vellus-like Hair
kenogen density. Marked in PHL. Is empty HF & miniaturisation evidence of (similar) chronologic aging process? (Mohungoo & Messenger, 2010)
10/31
Does Senescent Alopecia Really Exist?
Diagnosis: Complicated by overlapping AGA or diffuse alopecia (Whiting)
Definition: Onset >60y. HF miniaturization with distinctive altered gene expression (Mirmirani et al, 2007)
SA: FGF5; DST, ACTN2, TNNI3, PARVB; JAK2, PRKD3, AK2, TRAP1, TRIO, ATP12A,
MLL4, STK22B. Oxidative stress and inflammatory response genes
AGA: Wnt, βcatenin, TGFα, TGFβ, Stat-3,
Stat-1; PPARd, IGF-1, Notch, Msx2, KRTs,
KAPs; Msx2, Activin, IGF-1. BDNF, BMP2,
BMP7, VDR, IL-1, ER; RAR
11/31
Primary histologic finding of HF downsizing; drop-out not
detected using elastic tissue stains Price et al 2001
Others: SA cumulative degeneration of selected HF?
Immune-controlled programmed organ deletion? (as seen in healthy murine skin, Eichmüller et al 1998).
Do HFs ‘drop-out’ in Senescent alopecia?
AR & Aromatase: >60yr levels were low. Comparable in
frontal & occipital scalp with or without thinning.
5a-reductase type 1/2 not significantly in men with thinning
hair vs men without. SA may not be fully androgen-dependent
12/31
IRF4 (Interferon-regulatory factor 4)
– 1st gene for gray hair
Baldness: Confirmed AR locus assoc.
but also SNPs in GRID1- role in hair biology?
Hair Aging Genes?
(Adhikari et al, 2016)
13/31
Acidification Theory of Aging
(Auto)-Immune Theory
Caloric Restriction Theory (worms only?)
Cross-Linking Theory (AGEs)
Death Hormone Theory (DECO)
DNA Damage Theories – accumulated DNA damage; replication errors,
ROS, eroded telomeres, chromosome breaks cellular senescence or
apoptosis (endo/exogenous sources)
Free Radical Theory
Hayflick Limit Theory
Mitochondrial Decline Theory
Neuro-endocrine Theory
Redundant DNA Theory
Thymic-Stimulating Theory
"Wear and Tear" Theory
Aging: Theories
14/31
18 mo (~62 yr) 24 mo (~70yr) 30 mo (~85 yr)
8 mo
12 mo
24 mo (H)
DDR - Transepidermal Elimination of HFSC
via COL17A1 Proteolysis leads to HF ‘aging’
24 mo (HL)
HF count after 12 mths (~58yr). HF miniaturization with dermis
Matsumura et al, 2016 15/31
Down-regulation of HFSC Signature
Precedes HF Miniaturization/Hair Loss During Aging
Matsumura et al, 2016
16/31
HF Aging by Trans-epidermal Elimination of Stem Cells
via COL17A1 Proteolysis
Matsumura et al, 2016
DDR-induced COL17A1deficiency drives HF
miniaturization - only very few HFs lost with aging? 32 mth (89y)
17/31
33yo F 68yo F Normal Mini
COL17A1/ K15/ DAPI
Human HF miniaturization
with loss of COL17A1 mimics Mouse HF Aging
Matsumura
et al, 2016
22y Epidermis 70y Epidermis
γH2AX/ K15/ DAPI
Bulge Bulge
γH2AX: DNA
ds breaks
18/31
■ KRT15hi HFSC preserved, but CD200hi
/ITGA6hi & CD34hi progenitors in bald scalp
Is it all about the stem cells? If so – which ones?
Garza et al, 2011; Ruzankina et al, 2007
■ Alopecia & canities in ATR ko mice:
tissue-specific stem/progenitor cells,
regenerative capacity
■ Restoration of HFSC pools before
irreversible tissue changes tissue
regeneration & anti-aging in skin/HF?
■ Deletion of DDR genes premature
age-related phenotypes?
19/31
Age vs Menopause: growth rate, density, % anagen, diameters greater in frontal vs occipital scalp (Mirmirani et al 2010)
Scalp hair density with age, but not markedly affected by menopause status
Frontal hair calibre in post-menopause - age independent.
Is HF Aging Different in Women?
hair calibre vs age (frontal)
hair growth rate vs age (frontal)
age
age
hair count vs age
age
20/24 20/31
Does Hair growth Duration (Anagen) or Hair Cycle
Frequency affect HF Aging?
Xie Qiuping, China
2004 growing hair
since 1973, 5.6 m.
■ Is prolonged TA division possible without HFSC?
Continuous melanin synthesis without McSC?
■ Why is canities onset age so variable (incl. on
same scalp) – really down to embryologic legacy?
■ Anagen duration/fiber caliber. Kenogen.
Maximal hair length with age. Hairs/ unit area.
■ Irregular course (stability/partial remission/marked
evolution) Courtois et al, 1995
■ Eyebrow HF: 6mth hair cycle.
x6-10 cycles than scalp HFs
but still appear ‘younger’?
21/31
Hair growth cycle - driver of hair pigmentation aging
(Tobin, 2008)
Telogen
Early Anagen
Full Anagen
Early Catagen Mid Catagen Late Catagen
*G
*G
22/31
Are Gray HF Intrinsically/Extrinsically Distinct?
■ White HFs grow faster than pigmented HFs
~10% faster (Van Neste & Tobin: Micron, 2004)
■ Gray HF: altered Kc differentiation – melanin role?
Melanin Ca2+ load & may hasten Kc differentiation
Gray hair initially coarser, diameter & medulla
Mu
MU
PC
FP
PC
FP
23/31
‘Free radical theory’ (Arck, Peters et al, 2006)
Apoptosing bulbar MC; 8-OHdG byproducts; loss of Bcl-2/Kit.
HFMc sensitive to MtDNA deletion ( in graying HFs)
Catalase (Kauser et al, 2008, 2010)
catalase activity in gray HF; Anti-oxidants catalase activity
H2O2-mediated oxidative stress (Wood et al, 2009)
mM H2O2 in gray/white hair fibers & tyrosinase inhibition
Low catalase with decreased Met-S=O repair in gray HF
HF Aging & Oxidative Stress
Old
- high oxidative stress
Less efficient melanogenesis,
DNA/protein repair, anti-oxidants,
(Bcl2, SOD, Catalase etc.)
Young
- low oxidative stress
Efficient melanogenesis, DNA/
protein repair, anti-oxidants
(Bcl2, SOD, Catalase) White Hair Shaft
Tyrosinase Protein
24/31
Catalase Expression in Aging Human HFs
Kauser et al,
2011
Endogenous H2O2 Catalase in Young not Aged Donor HFM
67
45
42 kDa Actin re-probe
Catalase
Buthionine sulfoximine (BSO; glutathione depletor) @10-5 M, 48h
* * * *
FP M
65y
F
P
M
23y
FP
M
55y
25/31
Antioxidants: Catalase Activity & Cell Survival of ROS-stressed Aged-donor HFMc
Ctrl BSO BSO
+
Vit E
BSO
+
Quer
BSO
+ Vit E
+ Quer
0
20
40
60
80
100
60.4
73.6 74.4
88.2
** ** **
**
% S
urv
ival
Survival
0
10
20
30
40
50
60
Ca
tala
se
Ac
tiv
ity
m
ole
s/m
in/m
l
Ctrl BSO BSO
+
Vit E
BSO
+
Quer
BSO
+ Vit E
+ Quer
n/s ** **
**
32.9 33.9
39.7 40.1
50.4 Catalase Activity
(n= 5) ** P<0.01
Vit E @10-5 M; Quer @10-6 M; BSO@10-5 M (48h)
26/31
Extrinsic Aging Influence - Smoking
C57BL/6 mice: Developed hair loss when exposed to cigarette smoke (D’Aggostini et al, 2007)
Apoptosis in hair bulbs at hair loss edge - prevented by oral N-acetylcysteine.
Mechanism: Constricted cutaneous micro-vasculature. Impaired circulation & wound healing in hair restoration surgery in smokers (Tur et al, 1992, Yin et al, 2000)
Smoking: Linked with premature AGA & Canities Twin studies (Treub 2003; Yeo et al, 2014; Su et al, 2007 etc.)
27/31
Clues from the Literature • (x-)irradiation therapy for cancer
• After etretinate therapy • Steroid treatment & erythrodermic eczema • Post-inflammatory; PUVA etc.
+IBMX
(Tobin, 2006)
Yrs before diagnosis At diagnosis
• Porphyria cutanea tarda
HFMc isolated from white HFs
Skin and HF Aging Reversal - possible ?
28/31
Reversal of Skin & HF Reversal - possible ?
■ Reversal of skin aging: apoptosis & Fas.
Ki-67
TUNEL
Pre-graft) Post-graft
Gilhar et al, 2004
HF aging reversal in young host?
Cao et al, 2016;
Also Chen et al, 2014
29/31
Who has the oldest hair follicles?
Nature
515,
346–347
(20 November 2014)
Nature
515,
346–347
(20 November 2014)
HF aging… it’s all a bit
metaphysical
102 yrs
17yrs
30/31