Summary
Reviewed
abbreviations:
sen = senescent/senescence
sasp = senescence associated secretory phenotype
SCs = senescent cells
mt = mitochondria(l)
inflamm = inflammation/inflammatory
degen = degeneration
AD = alzheimers disease
BMD = bone mineral density
ER = endoplasmic reticulum
ox stress = oxidative stress
ox phos = oxidative phosphorylation
ROS = reactive oxygen species
CR = calorie restriction
inc = increase
dec = decrease
esp = especially
CVD = cardiovascular disease
T2D = type 2 diabetes
epidem = epidemiology/epidemiological studies
wt = wild type
KO = knockout
Summary 1
, AGE = advanced glycation end product
common mechanisms
Summary 2
, models
aging = occurs in all species and all members of a species, distinct from
age associated disease, could be defined on many levels from
chronological/biological/social
hallmarks can be primary (causing aging), antagonistic (in response to
damage) or integrative (consequences of aging)
aging combo of environmental factors, stochastic factors, extrinsic and
intrinsic damage, and disease specific factors all influencing hereditary
genetics, eg. recent biobank study found 17% mortality could be explained
by ‘exposome’ of 25 common environmental exposures = max lifespan
determined by intrinsic factors, average by extrinsic - why average
lifespan has dramatically increased but max relatively hasn’t
in humans difficult to separate effect of genes from environment, though
eg. twin studies, progeroid syndromes are useful > animals allow better
control of heterogeneity and manipulation of lifestyle factors, as well as
potential for gene manipulation to identify gerontogenes (genes that may
modify aging by inc/dec normal cell efficiency) eg. c.ele daf (IGF1R)
mutation almost doubled max lifespan, but not perfectly translatable as
animals vastly different lifespan and genomes to humans
some evolutionary aging theories suggest that aging occurs by genetic
design, and the decline in x is pre-programmed in an adaptive response >
however no evidence that specific genes cause aging directly, probably
rather influence other mechanisms, most theories suggest it is not
programmed but rather a passive side effect of evolution due to the force
of natural selection declining with age eg. disposable soma - evidenced in
ability of extrinsic factors and environment/lifestyle to largely modulate
lifespan as we have seen in the consistent rise in LE and numbers of
centenarians > lead onto interventions, how continued improvements in
mortality rates can be seen with interventions, even at older ages eg. 2024
study of veterans measured effect of 8 lifestyle changes (eg. exercise,
never smoking) on lifespan over 9yr period, found statistical inc in years
added with every additional change, up to >20yrs extra
Summary 3
, aging population (inc proportion of older people with >60 already
outnumbering <5) = from declining fertility and inc life expectancy with no
sign of plateau (from epidem transition decreasing preventable
mortality/compressing mortality so death now an old age phenomenon and
most causes of death chronic age-related disease) > as well as affecting
individual, effects on socioeconomic activity and healthcare system (eg.
inc age related disease burden), increasing recognition of need/urgency
for better aging support/understanding eg. UN decade of healthy aging
-2030 = focus on making healthspan match lifespan rather than further
extending life expectancy - ‘life to years’ not just ‘years to life’
senescence
in early cell culture, all cells are dividing so number of cells remains
constant across multiple passages > however, at a certain point (specific
to different cell types), accumulated population doublings reaches a
plateau (hayflick limit) as cells stop dividing in process = senescence
cells ‘keep track’ of their divisions through telomeres, ~5kbp regions of
repetitive, double stranded nucleotide sequences that form closed loops at
each end of chromosomes
help to solve the end replication problem: DNA polym fully replicates the
leading strand, but is unable to complete the lagging (3’) strand due to
absence of primer for final okazaki fragment > telomeres act as a a buffer,
progressively shortened with each division in place of valuable gene-
coding DNA
however, after multiple divisions, chronic erosion leads to the telomeres
becoming uncapped and unable to bind to shelterin protective complex or
form loops = chromosome end now resembles a DNA strand break,
triggering the DDR and activation of p53, ATM or p16INK4A etc to arrest
cell division in G1
in some cells eg. stem/embryonic, telomerase may be able to
extend/repair telomeres to reverse the arrest, but in most this marks
replicative senescence - permanent, stable arrest of division = can also be
triggered by ROS-DNA damage, mt dysfunction, SIRT depletion or inflamm
= almost all tissues show inc in correlation with age
Summary 4
Reviewed
abbreviations:
sen = senescent/senescence
sasp = senescence associated secretory phenotype
SCs = senescent cells
mt = mitochondria(l)
inflamm = inflammation/inflammatory
degen = degeneration
AD = alzheimers disease
BMD = bone mineral density
ER = endoplasmic reticulum
ox stress = oxidative stress
ox phos = oxidative phosphorylation
ROS = reactive oxygen species
CR = calorie restriction
inc = increase
dec = decrease
esp = especially
CVD = cardiovascular disease
T2D = type 2 diabetes
epidem = epidemiology/epidemiological studies
wt = wild type
KO = knockout
Summary 1
, AGE = advanced glycation end product
common mechanisms
Summary 2
, models
aging = occurs in all species and all members of a species, distinct from
age associated disease, could be defined on many levels from
chronological/biological/social
hallmarks can be primary (causing aging), antagonistic (in response to
damage) or integrative (consequences of aging)
aging combo of environmental factors, stochastic factors, extrinsic and
intrinsic damage, and disease specific factors all influencing hereditary
genetics, eg. recent biobank study found 17% mortality could be explained
by ‘exposome’ of 25 common environmental exposures = max lifespan
determined by intrinsic factors, average by extrinsic - why average
lifespan has dramatically increased but max relatively hasn’t
in humans difficult to separate effect of genes from environment, though
eg. twin studies, progeroid syndromes are useful > animals allow better
control of heterogeneity and manipulation of lifestyle factors, as well as
potential for gene manipulation to identify gerontogenes (genes that may
modify aging by inc/dec normal cell efficiency) eg. c.ele daf (IGF1R)
mutation almost doubled max lifespan, but not perfectly translatable as
animals vastly different lifespan and genomes to humans
some evolutionary aging theories suggest that aging occurs by genetic
design, and the decline in x is pre-programmed in an adaptive response >
however no evidence that specific genes cause aging directly, probably
rather influence other mechanisms, most theories suggest it is not
programmed but rather a passive side effect of evolution due to the force
of natural selection declining with age eg. disposable soma - evidenced in
ability of extrinsic factors and environment/lifestyle to largely modulate
lifespan as we have seen in the consistent rise in LE and numbers of
centenarians > lead onto interventions, how continued improvements in
mortality rates can be seen with interventions, even at older ages eg. 2024
study of veterans measured effect of 8 lifestyle changes (eg. exercise,
never smoking) on lifespan over 9yr period, found statistical inc in years
added with every additional change, up to >20yrs extra
Summary 3
, aging population (inc proportion of older people with >60 already
outnumbering <5) = from declining fertility and inc life expectancy with no
sign of plateau (from epidem transition decreasing preventable
mortality/compressing mortality so death now an old age phenomenon and
most causes of death chronic age-related disease) > as well as affecting
individual, effects on socioeconomic activity and healthcare system (eg.
inc age related disease burden), increasing recognition of need/urgency
for better aging support/understanding eg. UN decade of healthy aging
-2030 = focus on making healthspan match lifespan rather than further
extending life expectancy - ‘life to years’ not just ‘years to life’
senescence
in early cell culture, all cells are dividing so number of cells remains
constant across multiple passages > however, at a certain point (specific
to different cell types), accumulated population doublings reaches a
plateau (hayflick limit) as cells stop dividing in process = senescence
cells ‘keep track’ of their divisions through telomeres, ~5kbp regions of
repetitive, double stranded nucleotide sequences that form closed loops at
each end of chromosomes
help to solve the end replication problem: DNA polym fully replicates the
leading strand, but is unable to complete the lagging (3’) strand due to
absence of primer for final okazaki fragment > telomeres act as a a buffer,
progressively shortened with each division in place of valuable gene-
coding DNA
however, after multiple divisions, chronic erosion leads to the telomeres
becoming uncapped and unable to bind to shelterin protective complex or
form loops = chromosome end now resembles a DNA strand break,
triggering the DDR and activation of p53, ATM or p16INK4A etc to arrest
cell division in G1
in some cells eg. stem/embryonic, telomerase may be able to
extend/repair telomeres to reverse the arrest, but in most this marks
replicative senescence - permanent, stable arrest of division = can also be
triggered by ROS-DNA damage, mt dysfunction, SIRT depletion or inflamm
= almost all tissues show inc in correlation with age
Summary 4
