The Biology of Aging

Sophie Tatishvili

CHRONOLOGICAL CATEGORIES
Young-Old - (ages 65 - 74)
Chronological age - number of years lived
Physiologic age - age by body function Middle-Old - (ages 75 - 84)
Functional age - ability to contribute to society
Old-Old - (age 85 and older)

Biological aging is a multifactorial process. The molecular hallmarks of aging and

The call-out blue boxes indicate organ-specific physiological function are both influenced by genetic, epigenetic, and
factors that might delay the aging environmental factors. Metastatic aging may contribute to differential aging in
process including nutrient response
pathways and, possibly, adaptive
remote tissues through a paracrine mechanism.
evolutionary effects.
Biological aging is associated with a reduction in the reparative
Aging is seen as the random degeneration and regenerative potential in tissues and organs. This reduction
resulting from the inability of evolution to manifests as a decreased physiological reserve in response to
prevent it, i.e., the non-adaptive stress (termed homeostenosis) and a time-dependent failure of
consequence of evolutionary “neglect.” This complex molecular mechanisms that cumulatively create
conclusion is supported by studies that disorder. Aging inevitably occurs with time in all organisms and
restricted reproduction to later life in the emerges on a molecular, cellular, organ, and organismal level
fruit fly, Drosophila melanogaster, thus with genetic, epigenetic, and environmental modulators.
permitting natural selection to operate on Individuals with the same chronological age exhibit differential
later life traits and leading to an increase in trajectories of age-related decline, and it follows that we should
longevity. assess biological age distinctly from chronological age.

Molecular and physiological manifestations and measurement of aging in humans. May 2017.
Harrisson. Internal Diseases. 19th edition. Aging cell 16(4). DOI: 10.1111/acel.12601. License CC BY 4.0. Project: PAI-1 and Aging
The typical features of aging Major Theories of Aging
The typical features of aging (aging phenotype and exponential • Accumulation of damage to information molecules
increase in risk of death) are not universal findings in living
things. Some living things (e.g., rockfish and the bristlecone (spontaneous mutagenesis, errors in DNA, RNA and
pine, sometimes called the Methuselah tree) undergo negligible protein synthesis, superoxide radicals, etc).
senescence, whereas others die almost immediately after
reproduction is completed (e.g., semelparous animals and
annual plants). • Regulation of specific genes (appearance of specific
There are some species of plants and animals that do not appear proteins).
to age, or at least they undergo an extremely slow aging process,
termed “negligible senescence.” The mortality rates of these
species are relatively constant with time, and they do not display19 • Depletion of stem cells (convergence of above
any obvious phenotypic changes of aging. Conversely, there are
some living things that undergo programmed death immediately mechanisms).
after reproduction, such as annual plants and semelparous
animals.
Harrisson. Internal Diseases. 19th edition.

Aging and death theories can be classified

Theories OF AGING
into two groups:
(1) causality theories which address
questions of how aging and death occur
and can be subdivided into entropy-based
processes and “sudden death.” (2)
Evolutionary theories which try to explain
why species age and die in the way they do.
They consist of programmed aging, non-
programmed aging and senemorphic aging
which is a special case where parallel
evolution of “senemorphisms” (independent
aging phenotypes encoded by the genome)
are related to both a genetic profile to
accelerate aging and a genetic profile to
maximize lifespan.

• November 2003 Journal of Applied Physiology 95(4):1706-16 DOI: 10.1152/japplphysiol.00288.2003 Front. Genet., 06 March 2013 | https://doi.org/10.3389/fgene.2013.00025
 Relationship of telomere attrition to
Evolutionary theory
human aging-related diseases
• Organisms can generally evolve characteristics that act to improve
their ability to evolve and adapt to external circumstances by changing
the genetic design of subsequent generations. If aging is a design Telomere attrition is depicted
as an underlying, shared,
feature, there might be increased benefit if a species could regulate life interactive contributor to the
span. For example, the life spans of individual animals having the etiologies of aging and aging-
same genetic design could be adjusted to compensate for external related diseases. Because both
nongenetic and genetic
conditions. influences affect it, telomere
maintenance is a malleable
and integrative indicator of
overall health.

Science 04 Dec 2015: Vol. 350, Issue 6265, pp. 1193-1198

R.L.Kane. J.G.Ouslander, I.B.Abrass, B.Resnick. Essentials of Clinical Geriatrics. 7th Ed
DOI: 10.1126/science.aab3389

Mammalian energy-sensing pathways implicated in dietary Autophagy

interventions.
A complex crosstalk exists between the energy-sensing pathways in There are a number of ways that cells can remove damaged
mammals. The complexes of the mTOR pathway, TORC1 and TORC2 are
macromolecules and organelles, often generating cellular energy as a
activated by signals of high nutrient availability. TORC1 is stimulated by the
presence of amino acids, growth factors including insulin, ATP, and byproduct. Intracellular degradation is undertaken by the lysosomal
glycolysis metabolites. TORC2 is also activated by growth factor signaling system and the ubiquitin proteasomal system. Both are impaired with
including insulin and EGF and further activates TORC1 through Akt. aging, leading to the accumulation of waste products that alter cellular
Together, TORC1 and TORC2 stimulate cell growth and proliferation
through the inhibition of cell maintenance pathways such as autophagy,
functions. Such waste products include lipofuscin, a brown
and the stimulation of global protein synthesis. Conversely, AMPK inhibits autofluorescent pigment found within lysosomes of most cells in old
TORC1 and is activated by a low energy status in the cell. AMPK also age and often considered to be one of the most characteristic histologic
contributes activate the sirtuins, including SIRT1 and SIRT3, and is in turn
features of aging cells. They also include aggregated proteins
further activated by SIRT1. SIRT1 leads to the activation of PGC-1 α . PGC-1
α activation induces the transcription of many important genes involved in characteristic of age-related neurodegenerative diseases (e.g., tau, β-
mitochondrial biogenesis and regulation, including Nrf-1, and Nrf-2, which amyloid, α-synuclein). Lysosomes are organelles that contain
induce expression of TFAM, and also further transcriptionally activates itself proteases, lipases, glycases, and nucleotidases that degrade intracellular
TOR kinase and AMPK are major upstream regulators of mitochondrial and SIRT3. Meanwhile, SIRT3 activates FoxO3, which induces the macromolecules, membrane components, organelles, and some
metabolism, a regulation that offers an essential contribution to mediate CR- expression of key ROS antioxidants such as SOD2 and catalase as well as key
induced longevity. Dysregulation of TORC1 signaling plays a major role in many genes involved in autophagy. SIRT1 further activates autophagic machinery
pathogens through a process called autophagy. The lysosomal process
cancers as well as many diseases associated with aging by deacetylation of key atophagic components. most impaired with aging is macroautophagy, which is regulated by
Activation of autophagy can consequently activate mitophagy, leading to selective clearance of damaged or unfit numerous autophagy-related genes (ATGs). Old age is associated with
• May 2015 Biochimica et
mitochondria. In the mitochondria, SIRT3 also deacetylates many proteins including complexes of the electron Biophysica Acta 1847(11) some impairment in chaperone-mediated autophagy, whereas the effect
transport chain, MPTP component cyclohpilin D, and SOD2, resulting in greater respiratory efficiency, apoptotic • DOI: 10.1016/j.bbabio.201
5.05.005
https://doi.org/10.1016/j.celrep.2014.07.061
of aging on the third lysosomal process, microautophagy, is unclear.
resistance, and ROS protection. Arrows indicate activation. T bars indicate suppression. Harrisson. Internal Diseases. 19 edition.th
Mitochondrial dysfunction during aging and age-
related disorders.
Epigenetic control of gene expression
Aging is associated with progressive
mitochondrial dysfunction that occurs due to There are three key epigenetic
accumulation of mitochondrial DNA (mtDNA) mechanisms that regulate gene
mutations and increased reactive oxygen species expression (i) methylation of CpG
(ROS) production that causes oxidative damage to islands, mediated by DNA
cellular macromolecules, thereby leading to methyltransferases, (ii) histone
reduced respiratory chain activity and adenosine protein modifications and (iii)
triphosphate (ATP) generation. Mitochondrial microRNAs. The various
fission and fusion play a vital role in the epigenetic modifications control
regulation of mitochondrial function, metabolism gene activation and silencing
and quality control. Altered mitochondrial affecting gene expression.
dynamics with chronological age can inhibit Abbreviations: CpG, cytosine
mitophagy leading to accumulation of damaged or phosphate guanine; meCpG,
dysfunctional mitochondria in cells. Moreover, methylated CpG island; DNMTs,
decline in mitophagy with increasing age DNA methyltransferases.
prevents
• December 2017 Genes 8(12) DOI:10.3390/genes8120398 The expression of miRNAs usually decreases with aging and is Clinical ScienceJan 27, 2015,128(9)537-558;DOI: 10.1042/CS20140491

altered in some age-related diseases

Environmental factors, metabolic disease and

aging
Inflammaging and Immunosenescence

Environmental factors, metabolic disease and Increasing age leads to elevated basal
aging induce epigenetic modifications leading levels of inflammation (inflamm-aging)
to altered gene expression and subsequent and increased immunosenescence, which
dysfunction of BM-derived angiogenic cells. are associated with changes in both innate
Extracellular microvescicles also represent and adaptive immune responses,
important carriers of adverse epigenetic signals. contributing to the heightened morbidity
Reprogramming epigenetic changes by and mortality seen in the elderly.
chromatin modifying drugs and miRNAs Abbreviations: IL, interleukin; TNF,
modulators may represent a valuable approach tumor necrosis factor.
to restore functionality of circulating and
resident progenitor cells.

• November 2013 Clinical Interventions in Aging 8(default):1489-1496

University of Zurich 30 May 2017 Data Protection Statement DOI: 10.2147/CIA.S51152
Progeria: A rare genetic premature ageing Caloric restriction and the four hypotheses of
disorder aging Four major theories of aging; oxidative damage
attenuation hypothesis (green), glucose-insulin
hypothesis (yellow), growth hormone and
insulin-like growth factor (IGF)-1 (blue), and
the hormesis hypothesis (orange). Oxidative
damage is decreased during caloric restriction
(CR), through decreased production of reactive
oxygen species and the up-regulation of
protective enzymes, resulting in a decrease in
DNA damage and increase in genome stability.
CR causes decreased levels of circulating
insulin and glucose, resulting in decreased cell
growth and division, shifting toward
maintenance and repair. Decreased levels of
growth hormone and IGF-1 in response to CR,
promoting maintenance and repair. CR is
inducing a low level of stress which enables
cells to counteract higher stresses, increase
DNA repair gene expression and favor
maintenance and repair.

• May 2014 The Indian Journal of Medical Research 139(5):667-74 Source PubMed
• License CC BY-NC-SA 3.0 Front. Genet., 18 August 2016 | https://doi.org/10.3389/fgene.2016.00142

Spermidine is a physiologic polyamine that induces autophagy-mediated lifespan extension in yeast, flies, and worms.
Spermidine levels decrease during the life of virtually all organisms including humans, with the stunning exception of
Pharmacologic Interventions to Delay Aging and centenarians. Oral administration of spermidine and upregulation of bacterial polyamine production in the gut both

Increase Lifespan lead to lifespan extension in short-lived mouse models. Spermidine has also been found to have beneficial effects on
neurodegeneration probably by increasing transcription of genes involved in autophagy.
• Rapamycin, an inhibitor of mTOR, was originally discovered on Easter Metformin. Metformin, an activator of AMPK, is a biguanide
Resveratrol an agonist of SIRT1, is a polyphenol that is Island (Rapa Nui; hence its name) as a bacterial secretion with
antibiotic properties. Before its immersion in the antiaging field, first isolated from the French lilac that is widely used for the
found in grapes and in red wine. The potential of rapamycin already had a longstanding career as an treatment of type 2 diabetes mellitus. Metformin decreases
resveratrol to promote lifespan was first identified in immunosuppressant and cancer chemotherapeutic in humans. hepatic gluconeogenesis and increases insulin sensitivity.
yeast, and it might be responsible for the so-called French Rapamycin extends lifespan in all organisms tested so far, Metformin has other actions including inhibition of mTOR and
including yeast, flies, worms, and mice. However, the potential
paradox whereby wine reduces some of the utility of rapamycin for human lifespan extension is likely to be mitochondrial complex I and activation of the transcription
cardiometabolic risks of a high-fat diet. Resveratrol has limited by adverse effects related to immunosuppression, wound factor SKN-1/Nrf2. Metformin increases lifespan in different
healing, proteinuria, and hypercholesterolemia, among others. An mouse strains including female mouse strains predisposed to
been reported to increase lifespan in many lower order alternative strategy may be intermittent rapamycin feeding, which high incidence of mammary tumors. At a biochemical level,
species such as yeast, fruit flies, worms, and mice on was found to increase mouse lifespan.
metformin supplementation is associated with reduced oxidative
high-fat diets. In monkeys fed a diet high in sugar and fat, • In mammals, rapamycin is a potent inhibitor of TORC1, and also of damage and inflammation and mimics some of the gene
resveratrol had beneficial outcomes related to TORC2 at high doses or chronic treatments. Rapamycin treatment expression changes seen with caloric restriction.
drastically attenuates the detrimental effects of both high protein
inflammation and cardiometabolic parameters. Some and high fat diets in mice. Specifically, in mice a significant The proposed targets include activation of mitochondrial
studies in humans have also shown improvements in decrease in the amount and function of muscle mitochondria was respiratory chain complex I, AMPK, and SIRT1. In addition,
cardiometabolic function, whereas others have been seen following a life-long high-protein diet, which was reverted by metformin has recently been reported to inhibit mTOR, thereby
chronic treatment with rapamycin. Inhibition of mTOR by suggesting a potential overlap in the signaling pathways induced
negative. Gene expression studies in animals and humans rapamycin also activates selective degradation of unfit
reveal that resveratrol mimics some of the metabolic and mitochondria through mitophagy, a process critical for by both metformin and rapamycin
mitochondrial quality control.
gene expression changes of caloric restriction
• Mitophagy is essential for healthy aging since it has the potential of • Harrisson. Internal Diseases. 19th edition.
• May 2015 Biochimica et Biophysica Acta 1847(11)
Harrisson. Internal Diseases. 19th edition . eliminating mitochondrial genomes carrying OXPHOS-disabling • DOI: 10.1016/j.bbabio.2015.05.005
mutations.
The links between person-centred care, dignity and Hypertension in Elderly- ≥65 years
spiritual care • The prevalence of hypertension increases with age, with a prevalence of 60% over the age of 60 years and 75% over the age of 75
years.
• Discussion about the treatment of ‘the elderly’ or ‘older’ people has been complicated by the various definitions of older age used in
RCTs. For example, older was defined as >60 years in the earliest trials, then as 65, 70, and finally or 80 years in later trials.
Chronological age is often a poor surrogate for biological age, with consideration of frailty and independence influencing the likely
tolerability of BP-lowering medications.
• However, older patients are more likely to have comorbidities such as renal impairment, atherosclerotic vascular disease, and
postural hypotension, which may be worsened by BP-lowering drugs. Older patients also frequently take other medications, which
may negatively interact with those used to achieve BP control.
Person-centred care is currently the preferred • Data recently published from the SPRINT trial, which included a cohort of patients older than 75 years, in whom more intense BP
method of providing care 'that is responsive lowering reduced the risk of major CV events and mortality.
to individual personal preferences, needs and • However, in most RCTs showing a protective effect of BP-lowering treatment in patients with an untreated baseline BP in the grade
1 hypertension range, older patients were well represented.
values and assuring that patient values guide
• This was further supported by the recent HOPE-3 trial, which showed beneficial effects of BP lowering on CV outcomes in patients,
all clinical decisions' many with grade 1 hypertension (SBP >143 mmHg and mean BP = 154 mmHg), whose mean age was 66 years, and in whom only
22% had prior treatment of hypertension.
• The evidence supports the recommendation that older patients (>65 years, including patients over 80 years) should be offered BP
lowering treatment if their SBP is >_160 mmHg. There is also justification to now recommend BP-lowering treatment for old
patients (aged >65 but not >80 years) at a lower BP (i.e. grade 1 hypertension; SBP = 140–159 mmHg).201 BP-lowering drugs
should not be withdrawn on the basis of age alone. It is well established that BP lowering treatment withdrawal leads to a marked
increase in CV risk.
• In older hypertensive patients, treatment presents more difficulties than in younger people, because the decision to treat
hypertension must take into account the patient’s clinical condition, concomitant treatments, and frailty.
• A recent study of a cohort of older patients from the general population (thus including those with frailty) has shown that better
adherence to antihypertensive treatment was associated with a reduced risk of CV events and mortality, even when age was >85
years.

NHS Scotland, 2010: p22)

Escardio Guidelines for AH 2018
 Hypertension in Elderly cont. Heart Failure in The older adult, frailty and cognitive
impairment
• In all older patients, and especially very old or frail patients, the possible
occurrence of postural BP should be closely monitored and symptoms of possible
hypotensive episodes checked by ABPM. • Frailty is common in older adults with HF, with a recent study suggesting it
• Unless required for concomitant diseases, loop diuretics and alpha-blockers may be present in >70% of patients with HF and >80 years of age.
should be avoided because of their association with injurious falls. • Frailty scoring systems provide an objective assessment and identify the
• Renal function should be frequently assessed to detect possible increases in serum presence of or change in the level of frailty.
creatinine and reductions in eGFR as a result of BP-related reductions in renal • Patients with a high frailty score will benefit from closer contact with the
perfusion. When treated, BP should be lowered to a systolic value of 130–139 HF specialist team, more frequent follow-up and monitoring and
mmHg and a diastolic value of < 80 mm Hg if tolerated. individualized self-care support.
• Treated SBP values of <130 mm Hg should be avoided. • Frailty scores include: walking speed (gait speed test), timed up-and-go test,
• A key emphasis in treating older patients, and especially the very old, is to PRISMA 7 questionnaire, Frail Score, Fried Score and Short Physical
carefully monitor for any adverse effects or tolerability problems associated with Performance Battery (SPPB).
BP-lowering treatment, keeping in mind that adverse effects can be more frequent
than reported in RCTs, in which specific medical expertise and close patient • Cognitive function can be assessed using the Mini-Mental State
supervision may minimize adverse effects and tolerability problems. Examination.

Escardio Guidelines for AH 2018

Escardio Guidelines for HF 2016

Elderly and frail patients with Non-STEMI

• Recommendations • Classa Levelb
• It is recommended to tailor antithrombotic
treatment according to bodyweight and • I C
renal function.
• Elderly patients should be considered for
an invasive strategy and, if appropriate,
revascularization after careful evaluation • IIa A
of potential risks and benefits, estimated
life expectancy, comorbidities, quality of
life, frailty and patient values and
preferences.
• Adjusted dosing regimens of beta-
blockers, ACE inhibitors, ARBs and Iia C
statins should be considered to prevent
side effects.

Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology. 2015 ESC Guidelines for the management of acute coronary
syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the
European Society of Cardiology (ESC). Eur Heart J. 2016;37(3):267-315
 Elderly patients with STEMI
Syncope in patients with comorbidity and frailty
• These patients may present with atypical symptoms, the diagnosis of MI may be
delayed or missed.
• In addition, the elderly have more comorbidities and are less likely to receive • Older patients frequently have abnormal findings on more than one
reperfusion therapy compared with younger patients. investigation and may have more than one possible cause of syncope.
• Elderly patients are also at particular risk of bleeding and other complications from • Conversely, coincidental findings of cardiovascular diagnoses such as aortic
acute therapies because bleeding risk increases with age, renal function tends to stenosis or atrial fibrillation may not necessarily be the attributable cause of
decrease, and the prevalence of comorbidities is high. events.
• Observational studies have shown frequent excess dosing of antithrombotic therapies • The prescription of polypharmacy, cardiovascular medications, and
in elderly patients. psychotropic (neuroleptics and antidepressants) and dopaminergic drugs
• Furthermore, they have a higher risk of mechanical complications. also increases the risk of syncope and falls.
• It is key to maintain a high index of suspicion for MI in elderly patients who present • Negative dromotropic and chronotropic medications should be carefully
with atypical complaints, treating them as recommended, and using specific strategies evaluated in older patients presenting with syncope or falls.
to reduce bleeding risk; these include paying attention to proper dosing of • Syncopal events may be unwitnessed in over half of older patients meaning
antithrombotic therapies, particularly in relation to renal function, frailty, or that collateral histories may not available, which makes discrimination
comorbidities, and using radial access whenever possible. There is no upper age limit
with respect to reperfusion, especially with primary PCI. between falls and syncope challenging.
Escardio Guidelines STEMI 2018 Escardio Guidelines Syncope 2018
 Additional advice and clinical perspectives AF in Elderly
• In some frail elderly patients, the rigour of assessment will depend on compliance with tests and on prognosis. • Age is one of the strongest predictors/risk factors for ischaemic stroke in AF.
Otherwise, the evaluation of mobile, non-frail, cognitively normal older adults must be performed as for
younger individuals. • Good data are available to support the use of anticoagulants in older patients from
• Orthostatic BP measurements, CSM, and tilt testing are well tolerated, even in the frail elderly with cognitive BAFTA (Birmingham Atrial Fibrillation Treatment of the Aged Study), the NOAC trials,
impairment. and from analyses in elderly Americans (Medicare).
• Not infrequently, patients who present with unexplained falls— although orthostatic BP measurements, CSM, • The available data support the use of available rate and rhythm control interventions,
and tilt testing reproduce syncope—may deny TLOC, thus demonstrating amnesia for TLOC. including pacemakers and catheter ablation, without justification to discriminate by age
• Failure of orthostatic BP to stabilize is present in up to 40% of community-dwelling people >80 years of age group.
when BP is measured using phasic BP technology.
• Individual patients at older age may present with multiple comorbidities including
• Such failure of systolic BP to stabilize is a risk factor for subsequent falls and syncope. dementia, a tendency to falls, CKD, anaemia, hypertension, diabetes, and cognitive
• In the absence of a witness account, the differential diagnosis between falls, epilepsy, TIA, and syncope may dysfunction. Such conditions may limit quality of life more than AF-related symptoms.
be difficult.
• Impairment of renal and hepatic function and multiple simultaneous medications make
drug interactions and adverse drug reactions more likely.
• Transient loss of consciousness • Integrated AF management and careful adaptation of drug dosing seem reasonable to
• Carotid sinus massage reduce the complications of AF therapy in such patients.

Escardio Guidelines Syncope 2018 Escardio Guidelines Syncope 2016