REVIEWS

Ageing as a risk factor for

neurodegenerative disease
Yujun Hou   1, Xiuli Dan1, Mansi Babbar1, Yong Wei1, Steen G. Hasselbalch   2,
Deborah L. Croteau1 and Vilhelm A. Bohr   1,3*
Abstract | Ageing is the primary risk factor for most neurodegenerative diseases, including
Alzheimer disease (AD) and Parkinson disease (PD). One in ten individuals aged ≥65 years has
AD and its prevalence continues to increase with increasing age. Few or no effective treatments
are available for ageing-​related neurodegenerative diseases, which tend to progress in an
irreversible manner and are associated with large socioeconomic and personal costs. This Review
discusses the pathogenesis of AD, PD and other neurodegenerative diseases, and describes their
associations with the nine biological hallmarks of ageing: genomic instability , telomere attrition,
epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence,
deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication.
The central biological mechanisms of ageing and their potential as targets of novel therapies
for neurodegenerative diseases are also discussed, with potential therapies including NAD+
precursors, mitophagy inducers and inhibitors of cellular senescence.

Ageing is associated with physical deterioration that
leads to an increased risk of disease and death1. Ageing
occurs at different rates in different species, and inter-​
individual variations exist within a species and in the
different tissues of an individual2. Potential biomark-
ers of ageing align with the central molecular mech-
anisms of ageing, and studies have identified nine
critical hallmarks of the ageing process, as we discuss
in this Review2. Among the many risk factors for neuro­
degeneration, the ageing process itself has by far the most
impact. Thus, in order to develop successful interven-
tions, it is important to consider the basic mechanisms
of ageing and their role in the onset and progression of
neurodegenerative disease.
The US population aged ≥65 years is estimated to
increase from 53 million in 2018 to 88 million in 2050
(ref.3). As this elderly population increases, the financial
burden of age-​related health disorders will increase, and
1
Laboratory of Molecular
Gerontology, National
effective preventive and/or therapeutic approaches are
Institute on Aging, NIH, urgently needed. Among the different age-​related dis-
Baltimore, MD, USA. eases, neurodegeneration and the associated cognitive
2
Danish Dementia Research decline is particularly relevant owing to its great influence
Centre, Rigshospitalet, on healthspan and quality of life.
University of Copenhagen,
Given that in the elderly population, neurodegen-
Copenhagen, Denmark.
erative diseases are common and disease-​free brains
3
Center for Healthy Aging,
University of Copenhagen,
are rare, especially in very old individuals, brain age-
Copenhagen, Denmark. ing might form a continuum with neurodegeneration.
*e-​mail: vbohr@nih.gov Human genetic and environmental factors determine the
https://doi.org/10.1038/ progression of neurodegenerative disease4. It is tempt-
s41582-019-0244-7 ing, therefore, to regard neurodegenerative diseases as a
manifestation of accelerated ageing. Conversely, ageing
is a major risk factor for neurodegeneration4. The most
common neurodegenerative diseases, Alzheimer disease
(AD) and Parkinson disease (PD), are predominantly
observed in elderly individuals, and the risk of these
diseases increases with age (Fig. 1). Molecular studies
have revealed that brain tissue from older individuals
contains abnormal deposits of aggregated proteins such
as hyperphosphorylated tau (p-​tau), amyloid-​β (Aβ)
and α-​synuclein; however, it remains unclear whether
the levels of these deposits are linked with the degree
of cognitive impairment5. Some studies have indicated
that the risk of neurodegenerative disease is associated
with early developmental defects, showing that brain
structural changes might take place much earlier than
cognitive impairment6. MRI measurements of white
matter myelin water fraction and grey matter volume in
various brain regions of infants who were carriers of the
apolipoprotein E (APOE) ε4 allele, a major suscepti­bility
gene for sporadic (late-​onset) AD, were significantly diff­
erent from measurements in non-​carriers6. Exposure
to adverse environmental stimuli — such as trauma,
drugs or environmental toxins — during development
has been proposed to have consequences in later life
(for example, by affecting neuroplasticity)7.
Common age-​related neurodegenerative diseases and
their estimated prevalences, as reported in the primary
literature, are shown in Table 1. The prevalence of AD
in individuals aged ≥95 years in the USA is ~50%3,8,9
(Fig. 1a). Globally, PD prevalence increases steadily with

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Key points
• Ageing is the main risk factor for most neurodegenerative diseases, including
Alzheimer disease (AD) and Parkinson disease (PD).
• Tissues composed primarily of postmitotic cells, such as the brain, are especially
sensitive to the effects of ageing.
• Hallmarks of ageing — genomic instability, telomere attrition, epigenetic alterations,
loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated
nutrient sensing, stem cell exhaustion and altered intercellular communication —
correlate with susceptibility to neurodegenerative disease.
• NAD+ deficiency is a key biomarker for mitochondrial dysfunction, and agents that
elevate intracellular NAD+ have shown promising results against many features of
neurodegeneration.
• Genomic instability, mitophagy, cellular senescence, protein aggregation and
inflammation are being explored as therapeutic targets for neurodegenerative
disease.
age8,10 (Fig. 1b), and according to data from 2014, the
prevalence of amyotrophic lateral sclerosis (ALS) in
the USA increases with age up to 80 years11 (Fig. 1c). This
Review synthesizes current knowledge about the bio-
logical processes linked with normal brain ageing and
neurodegeneration and discusses promising therapeu-
tic avenues. The main focus is on the two most preva-
lent neurodegenerative diseases, AD and PD, but other
neuro­degenerative diseases that show important links
with ageing hallmarks are also discussed12.
The biology of ageing
Ageing is an inevitable and irreversible process, associ-
ated with readily identifiable and characteristic changes
in physical appearance and function in the individual
organism. Studies have defined molecular and cellular
processes and biomarkers that are associated with ageing
in diverse mammalian species and might be linked with
basic biological mechanisms underlying human ageing.
López-​Otin et al.13 identified nine so-​called ‘hallmarks
of ageing’ and categorized them into primary, anta­
gonistic and integrative hallmarks. These hallmarks are
widely used in the field of ageing research and beyond.
The primary hallmarks are genomic instability, telomere
attrition, epigenetic alterations and loss of proteostasis.
Genomic instability is considered to be a major driving
force of ageing and is the central focus of one of the dom-
inant theories of ageing14. The antagonistic hallmarks
— mitochondrial dysfunction, cellular senescence and
deregulated nutrient sensing — are compensatory or
antagonistic responses to the primary damage. Initially,
these responses mitigate the damage, but eventually
they can become deleterious themselves. The integrative
hallmarks — stem cell exhaustion and altered intercel-
lular communication — arise as a result of cumulative
damage induced by the primary and antagonistic hall-
marks and are ultimately responsible for the functional
decline associated with ageing (Fig. 2).
Tissues composed primarily of postmitotic cells, such
as the brain, which contains postmitotic neurons and
oligodendrocytes, are especially sensitive to the effects of
ageing, primarily because postmitotic cells are believed
to be more vulnerable to DNA damage than proliferat-
ing cells15. DNA damage increases with ageing, which
might be important in the aetiology of ageing-​associated
neurodegenerative processes. Limiting the progression
of neuronal ageing through diet and exercise might be
possible14. Ageing neurons frequently show evidence of
mitochondrial damage and dysfunction, both of which
are associated with neurodegenerative disease and with
normal ageing. This Review outlines aspects of our cur-
rent understanding of the molecular and cellular basis
of human ageing, with a focus on neurodegenerative
disease.
Primary hallmarks of ageing
Genomic instability and DNA damage. Several types
of DNA damage, including bulky adducts, abasic sites,
DNA single-​strand breaks, DNA double-​strand breaks,
base mismatches, insertions and deletions, are associated
with neurodegeneration16. Oxidative DNA damage from
endogenous reactive oxygen species (ROS) can increase
inflammation, accelerate ageing, and increase suscepti-
bility to cancer and neurodegenerative diseases17. The
five key DNA repair pathways are base excision repair
(BER), nucleotide excision repair (NER), mismatch
repair, DNA double-​strand break repair (DSBR) and
direct reversal16,18.
BER is the primary mechanism for the repair of small
DNA base modifications, such as oxidative base damage
and single-​strand breaks19. Mutations in BER pathway
genes cause a mutator phenotype, potentially increas-
ing the risk of neurodegeneration and ageing20,21. In the
first step in BER, a DNA glycosylase recognizes and
removes the damaged DNA base, leaving an abasic site.
BER proceeds via one of two BER subpathways, known
as short-​patch and long-​patch BER. The repair process
involves the following core steps: excision of the base,
incision, end processing and repair synthesis, including
gap filling and ligation22. In principle, BER can be recons­-
tituted in vitro using four proteins: a DNA glycosylase,
AP endonuclease 1 (APE1), DNA polymerase β (Polβ)
and DNA ligase III (Lig III)22.
DNA damage not only generates genomic instabil-
ity, but also initiates signalling cascades that permeate
throughout the cell. Persistent DNA damage induces
PARP1, increases PARylation (the formation of PAR
polymers at sites of DNA damage or DNA alterations),
and depletes NAD+. NAD+ is an essential cofactor for
sirtuins, DNA repair, mitophagy and mitochondrial
health. Sirtuin 3, sirtuin 1, and sirtuins 1 and 6 pro-
mote efficient BER, NER and DSBR, respectively23.
DNA damage promotes cellular senescence and inflam-
mation, which together exacerbate ageing-​related
neurodegeneration (Fig. 3).
Telomere attrition. Telomeres are regions composed of
DNA and protein at the ends of the linear chromosomes.
Telomeres become shorter as cells divide, unless either
the parental cell expresses telomerase or another mecha­
nism is present to prevent telomere attrition. Telomere
shortening causes cellular senescence and is probably
involved in organismal ageing. Defects in telomere
maintenance accelerate ageing in mice and humans13.
Further clarification of telomere-​related pathogenesis in
neurodegenerative diseases is greatly needed, as has been
discussed elsewhere24,25.
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a Alzheimer disease b Parkinson disease c Amyotrophic lateral sclerosis

600 2,500 25

Cases per 100,000 population

Cases per 100,000 population

Cases per 1,000 population
500 2,000 20
400
1,500 15
300
Women 1,000 10
200 Men
Men Women
100 500 5

0 0 0
9

9
9

0
0
–6

–7

–7

–8

–8

–9

≥9

–3

–4

–5

–6

–7
–4

–5

–6

–7

≥8
≥8
65

70

75

80

85

90

18

40

50

60

70
40

50

60

70
Age (years) Age (years) Age (years)

Fig. 1 | Neurodegenerative disease prevalence. a | Prevalence of Alzheimer disease per 1,000 men and women by age in
the USA3,8,9. b | Prevalence of Parkinson disease per 100,000 men and women by age globally8,10. c | Prevalence of amyotrophic
lateral sclerosis (ALS) per 100,000 population in the USA in 2014 (ref.11).

Epigenetic alterations. Epigenetic modifications includ- fission, removal of damaged proteins by proteases, and
ing methylation, PARylation and acetylation of DNA mitophagy. Among these mechanisms, mitophagy has
and histones collectively influence chromatin tertiary received particular attention in recent years.
structure. Epigenetic markers strongly influence chro- Mitophagy is a form of autophagy that selectively
matin activity and function, including transcription and degrades dysfunctional mitochondria and has a key
replication. Epigenetic age-​related mechanisms have role in preventing age-​related disease. One mitophagy
roles in pathologies associated with neurodegenerative pathway is the PTEN-​induced putative kinase protein 1
diseases26. The emerging field of epigenetics in neuro- (PINK1)–Parkin pathway, whereby PINK1 accumu-
degeneration and neuroprotection has been reviewed lates on the outer membrane of depolarized mito-
elsewhere27. chondria and recruits the E3 ubiquitin ligase Parkin,
which ubiquitinates and targets mitochondrial proteins
Loss of proteostasis. The balance between protein syn- and promotes degradation of damaged mitochondria.
thesis and degradation creates a steady state known as Autophagosomes fuse with lysosomes to form auto­
proteostasis. The maintenance of proteostasis in eukary­ lysosomes where the enveloped proteins and/or dam-
otic cells depends on proper regulation of the protea- aged organelles or organelle fragments are degraded.
some and on the process of autophagy13, as well as on Mutations in the genes encoding PINK1 or Parkin
the ubiquitination machinery and lysosomal system. lead to locomotor deficits in Drosophila melanogaster31
Ubiquitinated proteins are often destined for degrada- and early onset of recessive PD in humans32. A 2018
tion. Autophagy is an intracellular degradation system study suggested that the activation of mitophagy to
that facilitates lysosomal degradation of misfolded or clear damaged mitochondria is critical not only for
unfolded proteins and of damaged organelles, thereby mitochondrial quality control but also for mitigating
reducing secretion of inflammatory cytokines28. Increa­ inflammation, an important risk factor for neurodegene­
sed protein misfolding, aggregation and deposition are ration33. Mitophagy can also take place in a manner that
observed in many neurodegenerative disorders. is independent of PINK1 and Parkin through the regu­
lation of FUNDC1, NIX/BNIP3, AMBRA1, BCL-2-L-13
Antagonistic hallmarks of ageing or MUL1 (ref.34). Genetic and pharmacological induc-
Mitochondrial dysfunction and mitophagy. As highly tion of the mitochondrial receptor NIX restored mito-
metabolically active cells, neurons have high energy phagy in cell lines from patients with PINK1-related or
demands to perform neuronal activities and are particu- Parkin-​related PD35. AMBRA1-mediated mitophagy
larly sensitive to changes in mitochondrial function. The has a promising neuroprotective role by limiting ROS-​
production of ROS is amplified in damaged mitochon- induced dopaminergic cell death36. In D. melanogaster,
dria and is implicated in the normal ageing process and overexpression of MUL1 can attenuate PINK1 and
in a majority of known neurodegenerative diseases29. Parkin mutant phenotypes in dopaminergic neurons
Besides ATP production, mitochondria also have key and might compensate for the loss of these proteins37.
roles in several intercellular pathways, including lipid Growing evidence suggests that defects in mitophagy
biosynthesis, calcium signalling and cell apoptosis, all contribute to neurodegeneration34. As such, mitophagy-​
of which are central processes in the development of stimulating agents are being explored for potential
neuro­degenerative disease30. Brain mitochondrial func- therapeutic benefit in animal models of several human
tion becomes impaired with age and is believed to be a neurological diseases, as discussed below.
major and early contributor to the ageing process. Studies have indicated that nuclear DNA damage
Several quality control mechanisms are involved in can lead to mitochondrial dysfunction, suggesting the
maintaining optimal mitochondrial function, including existence of nucleus–mitochondria ‘crosstalk’ signal-
proteasome degradation, export of damaged proteins in ling38 in DNA damage responses (DDRs) (Fig. 4). The
mitochondria-​derived vesicles, mitochondrial fusion and mitochondrial unfolded protein response (UPR) is a

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Table 1 | Age-​related neurodegenerative diseases

Disease Prevalence Major symptoms risk factors Neuropathological
hallmarks
Alzheimer 5.7 million in the USA in Impairment of learning and Age, family history , genetics, history of Aβ plaques, neurofibrillary
disease 2018 (ref.3) memory , speech difficulties head trauma, female gender, vascular tangles, neuronal loss,
risk factors, environmental factors195–198 neuroinflammation
Parkinson 2–3% of the global Muscle rigidity , tremors, Environmental factors, genetics, male α-​Synuclein-containing
disease population aged alterations in speech and gait gender, ethnicity , age, psychiatric Lewy bodies and loss of
>65 years in 2017 (ref.10) symptoms199,200 dopaminergic neurons,
grey matter atrophy201
Amyotrophic 0.6 cases per million Progressive motor defects, with Physical activity , familial aggregation, TAR DNA-​binding protein
lateral sclerosis globally in 2016 (ref.202) muscle weakness, atrophy and environmental and occupational 43 aggregation
spasms exposure (for example, to pesticides,
solvents or heavy metals), smoking,
head injury , genetics202
Huntington 5–7 per 100,000 white Chorea, dystonia, loss of Genetic mutation in HTT, inheritance Striatal atrophy ,
disease people in 2007 (ref.203) coordination, cognitive decline, neuronal loss, psychiatric
behavioural difficulties symptoms204,205
Dementia with 1.3 million in the USA in Visual hallucinations, movement Age >50 years, male gender, family Lewy bodies and Lewy
Lewy bodies 2014 (ref.206) disorders, cognitive problems, history206 neurites
sleep difficulties, depression
Ataxia From 1 in 40,000 to 1 Cerebellar degeneration, Genetics (mutations in ATM gene) Ataxia and telangiectasias
telangiectasia in 100,000 live births immunodeficiency , radiation
worldwide in 2016 sensitivity , diabetes, cancer
(ref.207) predisposition
Cockayne 2–3 per million globally in Growth failure, neurological Genetics (mutations in CSA or CSB Growth retardation and
syndrome 2008 (ref.208) disorders, photosensitivity , eye gene) neurodegeneration
disorders, premature ageing

mitochondria-​to-nucleus signal transduction path- Cells with high levels of DNA damage become senes-
way. Mitochondrial stress results in dysregulated UPR, cent and stop proliferating. Owing to the high energy
which leads to neurodegeneration. Research into mecha­ demand and increased abundance of ROS in neurons,
nisms that facilitate communication between nuclear brain tissue can accumulate high levels of DNA damage,
and mitochondrial compartments will improve our which increases with age and age-​associated loss of DNA
understanding of ageing and neurodegeneration. repair capacity15,46. As postmitotic cells, neurons are par-
ticularly vulnerable to the accumulation of DNA lesions,
Cellular senescence. Cellular senescence, first identified and for DNA repair they primarily depend on non­
in fibroblasts by Hayflick in 1965 (ref.39), is a state of homologous end joining, an error-​prone pathway, rather
stress-​induced stable cell cycle arrest and a senescence-​ than homologous recombination, the other process that
associated secretory phenotype (SASP) that occurs with repairs DNA double-​strand breaks. Re-​entry into the cell
age. Cellular senescence can be considered a response cycle by neurons is commonly seen in pathological con-
that aims to maintain survival of healthy cells and remove ditions such as AD, and is followed by neuronal hyper-
damaged cells under conditions of stress40. Several senes- ploidy and synaptic failure47. Neurons with a persistently
cence pathways have been described, including stress-​ activated DDR pathway exhibit many features of cellular
induced premature senescence, replicative senescence, senescence and are referred to as senescence-​like neu-
oncogene-​induced senescence, and mitochondrial rons48. In a study in old C57BL/6 mice, which showed
dysfunction-​associated senescence41. Cellular senes- that DNA damage induces a senescence-​like state in
cence is initially a mechanism of tumour suppression mature postmitotic neurons in vivo, 40–80% of Purkinje
but might become a tumour initiation mechanism, cell neurons and 20–40% of cortical, hippocampal and
perhaps as a result of ageing42. SASP emerges when peripheral neurons had high levels of DNA damage, acti-
damaged or dying cells acquire pro-​inflammatory pro­ vated p38 MAP kinase, oxidative stress and senescence-​
perties that might promote tumour progression via the associated β-​galactosidase activity49. The researchers
expression of cytokines (such as IL-6 and IL-1), growth found that p21 serves as an important signal transducer
factors, chemokines and proteases43. Cells that undergo between the DDR and the senescence-​like phenotype in
mitochondrial dysfunction-​associated senescence have neurons, similar to its role in proliferation-​competent
reduced NAD+:NADH ratios, which promotes growth cells49. Another study suggested not only that the effi-
arrest and prevents IL-1-associated SASP formation44. ciency of DNA repair decreases with age, but also that
A 2019 study revealed that NAD+ metabolism is also more complex DNA repair mechanisms are used during
involved in the regulation of SASP through the high ageing, leading to more mutations being introduced50.
mobility group A (HMGA)–nicotinamide phosphoribo- These less efficient DNA repair processes are associated
syltransferase (NAMPT)–NAD+ signalling axis and that with ageing and cancer and might also have a role in
NAD+ metabolism governs the pro-​inflammatory SASP45. neurodegeneration50.

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Genomic
instability
AD PD HD ALS AT
Telomere Epigenetic
attrition alterations
AD PD HD ALS AD PD HD

Loss of Altered intercellular

proteostasis Ageing hallmarks communication
AD PD and AD PD HD ALS
neurodegeneration

Deregulated Stem cell

nutrient sensing exhaustion
AD PD HD AD PD HD

Mitochondrial Cellular
dysfunction senescence
AD PD AT AD PD HD ALS

Fig. 2 | Hallmarks of ageing. Nine hallmarks of ageing — genomic instability , telomere attrition, epigenetic alterations,
mitochondrial dysfunction, deregulated nutrient sensing, loss of proteostasis, cellular senescence, stem cell exhaustion
and altered intercellular communication — seen in the main neurodegenerative diseases. AD, Alzheimer disease;
ALS, amyotrophic lateral sclerosis; AT, ataxia telangiectasia; HD, Huntington disease; PD, Parkinson disease.

Autophagy is another essential process that is linked
with cellular senescence51, but whether autophagy pro-
motes or inhibits senescence is still under debate. On the
one hand, macro-​autophagy might help establish SASP
by facilitating the synthesis of secretory proteins51, but
on the other hand, inhibition of autophagy might further
promote senescence under some circumstances, such as
through ROS and p53 (ref.52,53). GATA4 has been reported
to be activated in response to DNA damage in a manner
that depends on the kinases ATM and ATR, and has vital
roles in triggering SASP and senescence by activating the
transcription factor nuclear factor κB (NF-​κB). In cells in
which senescence had been induced by DNA damage,
GATA4 protein abundance was found to be increased
owing to improved protein stability during senescence54.
Degradation of GATA4 depends on selective autophagy
and is suppressed during senescence. An age-​related
decline in autophagy is observed in the brain. However,
the mechanism connecting reduced autophagy and
senescence in the brain needs to be elucidated. Processes
linked with cellular senescence that might be involved
include telomere attrition, inflammation, autophagy defi-
ciency, chronic DDR, oxidative stress and mitochondrial
dysfunction55. As cellular senescence exacerbates ageing
and age-​related brain dysfunction, targeting of senescent
cells might be useful in patients with neurodegenerative
diseases, as discussed later in this article.
Deregulated nutrient sensing and altered metabolism.
Calorie restriction, which downregulates nutrient sig-
nalling pathways, extends lifespan in several species
including mice, and might have neuroprotective effects
in human tissues56. Major nutrient-​sensing pathways and
molecules include insulin, insulin-​like growth factor 1
(IGF1), mechanistic target of rapamycin (mTOR), AMP-​
activated protein kinase (AMPK) and sirtuins13. mTOR,
AMPK and sirtuins are being explored as therapeutic tar-
gets for neurodegenerative diseases. Metabolic dysfunc-
tion is frequently observed in patients with neurological
disease and might correlate with low NAD+ abundance,
mitochondrial dysfunction and oxidative stress57.
Integrative hallmarks of ageing
Stem cell exhaustion. Functional stem cells are needed
for optimal health in later life. However, stem cell func-
tion and proliferative capacity decline over an organism’s

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Stress

DNA repair DNA damage

DNA damage responses
BER
NER
DSBR PARP1
PARylation
SIRT3
SIRT1
SIRT1 and SIRT6
Inflammation
Mitophagy TNF
Mitochondrial Senescence
dysfunction p16 IL-1β
NAD+
p21

Sirtuins

Ageing and neurodegeneration

Fig. 3 | NAD+, DNA damage, mitophagy , ageing and neurodegeneration pathways. Stresses such as radiation and
viral infections have been reported to induce DNA damage. Cellular senescence and inflammation are the main DNA
damage responses. Senescent cells often show increased expression of p16, p21 and other factors. Activated microglia
and astrocytes release many pro-​inflammatory factors such as tumour necrosis factor (TNF) and IL-1β. In addition to
leading to DNA damage, such stresses lead to mitochondrial dysfunction, which induces ageing and neurodegeneration.
Accumulation of DNA damage might be particularly prevalent in the CNS because of high susceptibility to oxidative
stress and low DNA repair capacity in postmitotic brain tissue. Accumulating evidence suggests that deficiencies in the
base excision repair (BER), nucleotide excision repair (NER) and DNA double-​strand break repair (DSBR) pathways
induce ageing-​associated neurodegeneration. NAD+ is an essential factor that is required for cellular function and energy
metabolism. NAD+ has been shown to have many functions in vivo and in vitro, including induction of mitophagy , promotion
of DNA repair via sirtuins (SIRTs), and inhibition of PARylation, senescence and inflammation. Interestingly , increased
mitophagy activity promotes DNA repair and degradation of dysfunctional mitochondria; increased NAD+ levels suppress
these pathologies and could have beneficial effects in ageing and age-​related neurodegenerative diseases.

lifespan. This functional loss can be caused by age-​
related high levels of DNA damage, low DNA repair
capacity, defects in proteostasis, epigenetic deregula-
tion, mitochondrial dysfunction, telomerase inactivation
and/or cell senescence58. Stem cell function is improved
by increased expression of heat shock protein HSP70 or
forkhead transcription factor FOXO4, and by treatment
with rapamycin58. In aged animals, exposure to young
blood through heterochronic parabiosis improves stem
cell function in muscle, liver, spinal cord and brain, and
counteracts ageing and rejuvenates cognitive processes59.
Therefore, targeting of aged stem cell regeneration might
alleviate age-​associated neurodegenerative diseases.
Altered intercellular communication and immune func-
tion. Alterations in levels of hormones such as leptin,
ghrelin, insulin, adiponectin and IGF1 regulate neuronal
damage and neurodegeneration. The immune system is
essential for shaping the brain during development, and
both the nervous system and the immune system change
with age, so the loss of regulation of immune responses
in the brain is likely to be a factor in neurodegenera-
tion60. Improved understanding of the role of innate and
adaptive immune responses in neurodegenerative dis-
eases is important as such knowledge will be crucial to
developing effective immune-​based interventions60. New
evidence suggests that the pathological mechanisms of
neurodegenerative diseases might involve interactions
of microglia — the innate resident immune cells in the
CNS — with other glial support cells, such as astrocytes
and oligodendrocytes60. Regulatory T cells are important
not only for maintaining peripheral immune balance but
also for the tolerance and immune privilege of the CNS
itself61. Mast cells, microglia, T cells, oligodendrocytes
and the crosstalk between these cells are essential in
the function of the immune system and in preventing
neuro­degenerative disease60,62. The link between changes
in immune response with age and increased incidence
of neurodegenerative diseases in the ageing population
might provide important insights into this interaction.
Inflammation, a fundamental protective event
in response to any insult, becomes upregulated with
advanced age and can be divided into five categories:
low-​grade, controlled, asymptomatic, chronic and sys-
temic states63. Low levels of inflammation can have bene-
ficial effects, but uncontrolled or sustained inflammation

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can be harmful and result in age-​related chronic neuro-
degenerative diseases such as AD and PD64. Gene expres-
sion studies in ageing human brains have emphasized
the importance of inflammation in neurodegenerative
diseases65.
Chronic inflammation, persistent activation of
microglia, sustained elevation of pro-​inflammatory
mediators and increased oxidative stress are associated
with age-​related neurodegenerative diseases64–66. In
these conditions, hallmarks of chronic inflammation are
observed, including the persistent activation of microglia
and subsequent sustained release of pro-​inflammatory
mediators, and also increased oxidative and nitrosa-
tive stress. Activated microglia elicit ROS, nitric oxide
and pro-​inflammatory cytokines such as IL-1β, IL-6 and
tumour necrosis factor (TNF), leading to neuroinflam-
mation67. The production of ROS from dysfunctional
mitochondria and increased NF-​κB signalling that occur
with increased age potentiate NLRP3 inflammasomes
and subsequently lead to release of IL-1β in the brain,
NAD+ depletion,
Sirtuin dysfunction
Mitophagy
defects
Apoptosis
DNA
Nuclear
fragmentation
gene
mutations
Mitochondrial
complex
dysfunction
Neurodegeneration
Impaired
mitochondrial
biogenesis
Inactivation Mitochondrial
Dysregulation
of transcription of UPR stress
factors
Fig. 4 | Nuclear–mitochondrial signalling in neurodegenerative disease. NAD+ has
a pivotal role in cellular homeostasis and function. NAD+ levels decrease with age and
are reduced in age-​related diseases. Sirtuins are NAD+-dependent deacetylases that
consume NAD+. Sirtuin deficiency impairs mitophagy in many diseases, including
Alzheimer disease. Mutations in some nuclear genes, especially those that encode
mitochondrial proteins, destroy nuclear–mitochondrial interactions and lead to
mitochondrial dysfunction. The mitochondrial unfolded protein response (UPR) is a
mitochondria-​to-nucleus signal transduction pathway resulting in a series of protective
events for mitochondria. Mitochondrial stress results in dysregulated UPR , which leads
to neurodegeneration. Notably , mitochondrial biogenesis is controlled mainly from the
nucleus, as most proteins involved are encoded by nuclear genes. Fragmentation of
genomic DNA is an initial hallmark of apoptosis and a number of the crucial events in
apoptosis commence in the mitochondria. The crosstalk between the nucleus and
mitochondrial dysfunction might have a strong effect on neuronal function, tipping
the balance from neuronal health to neuropathology and neurodegenerative diseases.
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resulting in an ageing-​associated chronic inflamma-
tory response68. Aggregated Aβ fibrils in AD69, mutant
α-​synuclein in PD70, mutant huntingtin in Huntington
disease (HD)71 and the superoxide dismutase 1 (SOD1)
mutant protein SOD1G93A in familial ALS72,73 are capa-
ble of inducing secretion of IL-1β via NLRP3 inflam-
masome activation. Inflammation also exacerbates Aβ
deposition in AD, and both α-​synuclein truncation and
aggregation in PD, and might induce protein aggrega-
tion in HD and ALS74,75. In this way, a positive feedback
loop can occur between the enhanced inflammation and
accumulation of disease-​specific misfolded proteins in
neurodegenerative diseases.
Other factors reported to contribute to the inflam-
matory response and pathogenesis of neurodegenera-
tive disorders include age-​related sex steroid hormone
deficiency76, defective proteasome and autophagy degra-
dation systems77,78, cellular senescence79, increased oxida-
tive DNA damage and impaired DNA repair80, decreased
innate and adaptive immune system responses81, and
environmental stressors82. Targeting of these neuro­
inflammatory processes might be beneficial in age-​related
neurodegenerative diseases. Anti-​inflammatory drugs
are already an important therapeutic strategy in age-​
related neurodegenerative disease, but a further chal-
lenge is to develop drugs that can cross the blood–brain
barrier and have fewer adverse effects than current
strategies. Immunotherapies have shown promise in
reducing inflammation in transgenic mouse models of
neurodegenerative disease83,84. Non-​pharmacological
interventions, including calorie restriction and phys-
ical activity, have also been shown to exert an anti-​
inflammatory effect85,86. An improved understanding
of the relationship between the inflammatory process
and age-​related neurodegenerative diseases is needed for
future potential interventions.
Ageing and neurodegenerative disease
Alzheimer disease
AD is the most common neurodegenerative disease.
The main clinical features of AD are late-​life memory
and learning deficits, disorientation, mood swings and
behavioural issues. Defects in at least three proteins,
the amyloid precursor protein (APP), presenilin 1 and
presenilin 2, have been identified as risk factors for AD87.
Mutations in the genes that encode these proteins are
linked with familial (early-​onset) AD. Sporadic (late-​
onset) AD occurs with much higher (and increasing)
prevalence and is thought to reflect complex interac-
tions between genetic and environmental factors. The
APOE*ε4 allele has been identified as the most common
genetic risk factor for sporadic AD88.
Prominent molecular features of AD are Aβ plaques
and p-​tau neurofibrillary tangles (NFTs) in the brain89.
Aβ is a short abnormal proteolytic fragment (36–43
amino acids of APP) produced by sequential cleavage
of APP by β-​secretase and γ-​secretase90. The primary
causal factors leading to AD are still a matter of intense
debate, but might include cholinergic dysfunction, Aβ
plaques, tau aggregation, inflammation, DNA damage
and mitochondrial dysfunction. Acetylcholinesterase
inhibitors (donepezil, galantamine and rivastigmine) are
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approved by the FDA for the management of AD, but
only alleviate some symptoms and have limited ability
to prevent disease progression91.
The Aβ hypothesis proposes that Aβ accumulation
and toxicity is the triggering factor in AD. Aβ forms
oligomers and fibrils that accumulate in the brain to
form Aβ plaques, resulting in neuronal loss92. Many
potential anti-​Aβ drugs are under development, but
many have failed in clinical trials. P-​tau accumulates in
neurons in AD and causes neuronal dysfunction and is
therefore considered to be another potential cause of
AD89,93. The neuroinflammatory response — a brain
immune response caused by internal or external stress,
excessive oxidation and accumulation of Aβ plaques or
p-​tau — is a key driver of AD94 and results mainly from
abnormal activation of astrocytes and microglia, which
release pro-​inflammatory cytokines. Mitochondrial dys-
function and DNA damage might also be risk factors
for AD. The clinical failure of therapeutic approaches
based on the Aβ hypothesis suggests that other strategies
and/or novel targets are needed as the basis of successful
interventions in AD95.
Various model systems have been used to study AD,
including mouse, rat, Caenorhabditis elegans, D. melano­-
gaster and human induced pluripotent stem cells
(iPSCs)96–101 (Table  2). Transgenic mouse models of
AD express variants of APP, presenilin 1, presenilin 2,
tau, APOE or Aβ, or combinations of these and other
mutations (for example, APPswe/PS1ΔE9, 3×TgAD
or 5×FAD). C. elegans and D. melanogaster models of
AD include knockout or overexpression of C. elegans
or D. melanogaster genes, or cross-​species expression of
human transgenes (Table 2).
Evidence suggests that increased DNA damage and
decreased DNA repair exacerbate AD progression102.
BER protein expression is specific to tissue type, cell
type and cell age, and might decrease with disease pro-
gression in patients with AD. For example, levels of
expression of uracil DNA glycosylase, β-​OGG1 glyco-
sylase and Polβ are lower in post-​mortem brain tissue
from patients with AD than in brain tissue from age-​
matched controls without AD103. Null alleles of Polβ are
lethal during embryonic development and are associated
with neurodevelopmental defects in mice104. A new AD
mouse model was presented in 2015 (ref.104). The com-
monly used 3×TgAD mouse was crossed with a mouse
that had defective DNA repair owing to heterozygosity
for the gene encoding Polβ104. The authors showed that
the resulting 3×TgAD/Polβ+/− heterozygote displayed
increased synaptic and cognitive deficits, including
neuronal dysfunction and cell death, compared with
3×TgAD mice104, suggesting that DNA damage has an
important role in AD progression.
Telomere instability or shortening might also have
a role in AD. Defects in telomere maintenance acceler-
ate ageing in mice and humans13 and, in patients with
AD, are associated with cognitive impairment, amyloid
pathology and hyperphosphorylation of tau via oxidative
stress and inflammation24.
As mentioned earlier, epigenetic mechanisms con-
tribute to age-​related disease processes in humans.
Diverse phenotypes and biological processes, including
learning, memory and behaviour, are regulated by
epigenetic mechanisms13,105, and both epigenetic and
environmental factors are thought to influence suscep-
tibility to sporadic AD. The epigenetic modifications
include methylation, PARylation and acetylation of
DNA and histones, all of which have important roles
in AD. For example, regions of the human and primate
APP promoters are differentially methylated in tissue
and brain regions in a manner that correlates with
APP expression, and specific patterns of DNA methyl-
ation and hydroxymethylation (5-methylcytosine and
5-hydroxy­methylcytosine) are associated with features
of AD26. Hyperactivated PARP1 can result in PARylation
and might contribute to AD pathology106,107. Alterations
in the level of histones and their modification patterns
have been suggested to be involved in AD pathogenesis.
Aberrant localization of phosphorylated histone H3 in
the cytoplasm, hyperphosphorylation of histone H3,
and decreased levels of acetylated histone H4 in the hip-
pocampus in patients with AD have been reported108.
Levels of histone deacetylase 2 (HDAC2) and HDAC6
have been shown to be significantly increased in patients
with AD, but might be counterbalanced by HDAC inhib-
itors, as indicated in experimental models of AD and
other neurodegenerative diseases108. Ubiquitination
of tau proteins is also observed in cells from patients
with AD28. Studies have shown that protein aggrega-
tion occurs when soluble protein monomers form high
molecular weight oligomers, polymers and eventually
very large insoluble fibrils (for example, Aβ aggregates
in patients with AD)109. These protein aggregates impair
neuronal activity but the molecular mechanisms that
underlie this effect are not known.
Emerging evidence suggests that mitophagy is com-
promised in AD, resulting in accumulation of dys-
functional mitochondria110. Studies have shown that
mitophagy mitigates inflammation, thereby decreasing
the risk of AD, PD and other neurodegenerative dis-
eases33. A cross-​species analysis, including C. elegans and
mouse models of AD and human iPSC-​derived human
AD neurons, showed that mitophagy is defective in AD,
and that stimulation of mitophagy reverses memory loss
in AD nematodes and mice111.
Another ageing hallmark, cellular senescence,
increases susceptibility to AD, PD and other neuro­
degenerative diseases112–115 (Fig. 5). Deposition of Aβ
fibrils in AD is linked with increased expression of
p16INK4a and SASP-​associated factors112. Increased abun-
dance of senescent astrocytes, microglia and neurons,
and expression of senescence-​associated β-​galactosidase
activity (SA-​β-gal) is observed in brain tissue from AD
patients116. Studies have shown that the senescence-​like
neurons and senescent astrocyte, microglia or oligo-
dendrocyte progenitor cells are sources of oxidative and
inflammatory stress and negatively affect neighbouring
cells by inducing a similar phenotype117,118. On the basis
of these findings, the removal of senescent cells from the
brain would be expected to show beneficial effects. This
strategy has shown some success in AD research117,118.
Zhang et al. reported that the exposure of aggregating
Aβ to oligodendrocyte progenitor cells in culture can
induce cell senescence, and that the selective removal of
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Table 2 | Models for studying Alzheimer disease

organism Model genetic alterations
Mouse 96
hAPP models PDAPP mouse line: mice express hAPP695/751/770 with Florida mutation (V717F) at the
γ-​cleavage site under the regulatory control of the PDGFβ promoter
J20 mouse line: mice express hAPP695/751/770
TgCRND8 mouse line: mice express hAPP695, containing the Swedish double mutations (K670N/
M671L) at the β-​secretase cleavage site and V717F mutation at the γ-​secretase cleavage site
Tg2576, APP23 and RI.40 mouse lines: mice express hAPP695, hAPP751 and entire human APP
gene, respectively , containing the Swedish double mutations (K670N/M671L) at the β-​secretase
cleavage site
TASD-41 mouse line: mice express hAPP containing the Swedish double mutations (K670N/M671L)
at the β-​secretase cleavage site and London mutation (V717I) at the γ-​secretase cleavage site
Aβ models BRI-​Aβ40 or BRI-​Aβ42 mouse lines: mice express fused Aβ and BRI protein, causing amyloid formation
hAPP/PS1 models APPswe/PS1ΔE9 mouse line: mice express hAPP695 with Swedish mutation (K670N/M671L)
and PSEN1 with ΔE9 mutation
5XFAD mouse line: mice express hAPP with Swedish (K670N/M671L), Florida (I716V), and London
(V717I) mutation, and PSEN1 with M146L and L286V mutations
2xKI mouse line: mice express mAPP with Swedish mutation (K670N/M671L) and humanized Aβ
and express mPS1 with P264L mutation
Models with hTau TAPP mouse line: mice express hAPP695 containing Swedish mutation and human four-​repeat tau
with P301L mutation and without the amino-​terminal sequences
3xTg mouse line: mice express three mutated AD genes: hAPP695 containing Swedish mutation,
human four-​repeat tau with P301L mutation and without the N-​terminal sequences, and PS1 with
M146V mutation
Htau mouse line: mice express the entire human tau gene
Rat hAPP/PS1 rat model101 Rats express APP695 with the K670N/M671L mutations, hAPP minigene with the K670N/M671L
and V717F mutations and human PSEN1 with the M146V mutation
Caenorhabditis Knockout of Worms with deletion of APP family proteins (APP/APLP1/APLP2)
elegans C. elegans genes97
Worms with deletion of α-​secretase gene (ADAM10 or ADAM17)
Worms with deletion of β-​secretase gene (BACE1)
Worms with γ-​secretase complex gene (PSEN1/2, APH1, APH2 or PEN2)
Worms with deletion of tau gene
Overexpression of Worms express human Aβ: APL-1, APL-1 extracellular domain or APL-1 deletion of Go/E1/E2/E1 and
C. elegans genes97 E2 domain in head and tail neurons, ventral cord, hypodermis and supporting cells and vulva muscles
Worms express APL-1 neuronal expression
Worms express proteins γ-​secretase complex sel-12, ttx-3, egl-13, pen-2 and sel-12
Worms express α-​secretase protein adm-4
Expression of human Worms express hAβ1-42, dimer Aβ1-42, Met35Cys Aβ1-42
proteins in C. elegans97
Worms express human γ-​secretase complex proteins hPSEN1, hPSEN2, nicastrin, APH1, PEN2
Worm neurons express human tau variants tau (4R1N), V337M tau (4R1N), P301L tau (4R1N), R406W
tau (4R1N), Tau352 (4R1N), Tau352 pseudo-​hyperphosphorylated, Tau352 pseudo-​hypophosphorylated
Drosophila Expression of human Flies express hAPP, hBACE and D. melanogaster γ-​secretase presenilin (dPsn) containing AD mutations
melanogaster proteins: Aβ toxicity98 N141I, L235P and E280A
Flies express Aβ40/42 peptides fused with D. melanogaster necrotic gene sequence for secretion
Expression of human Flies express wild-​type hTau or hTau containing V337M and R406W mutations
proteins: tau toxicity98
Flies express phosphorylation-​resistant tau variants containing S2A/S11A or S262A mutation
Overexpression of Flies with overexpression of β-​secretase-like protein
D. melanogaster
genes: Aβ toxicity98 Flies with knockdown of ferritin

Silencing of Flies with loss of dtau or partitioning defective-1 (PAR-1)

D. melanogaster
genes98,99 Flies with genetic inhibition of copper-​importers (Ctr1C and Ctr1B) or inhibition of zinc importer
dZip1 to rescue Aβ42 pathogenesis
iPSCs iPSC-​derived iPSC-​derived neurons containing mutation at PSEN1 A246E, PSEN2 N141I, PSEN1 M136I, PSEN1 ΔI4,
neurons100 PSEN1 Y115C, PSEN1 ΔE9, APP duplication, APP V717I
Aβ, amyloid-​β; AD, Alzheimer disease; APP, amyloid precursor protein; hAPP, human APP; iPSC, induced pluripotent stem cell.

Nature Reviews | Neurology

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Senescent Telomere
microglia shortening
↑ AD, PD ↑ AD, PD, HD
Senescent SA-β-gal
astrocytes
↑ AD, PD,
↑ AD, PD HD, ALS
Cellular
senescence
Senescent DDR
neurons
↑ AD, PD,
↑ AD, PD HD, ALS
SASP factors
p16INK4a
↑ AD, PD,
↑ AD, PD
ALS, HD
SASP inhibitors
Immunotherapeutics
Apoptosis inducers
Reactivation modulators
Fig. 5 | Cellular senescence and neurodegeneration.
Cellular senescence is increased in Alzheimer disease (AD),
Parkinson disease (PD), amyotrophic lateral sclerosis (ALS)
and Huntington disease (HD). A number of cellular
senescence markers, including senescent microglia,
senescent astrocytes, senescent neurons, senescence-​
associated secretory phenotype (SASP) factors, telomere
shortening, persistently activated DNA damage response,
increased SA-​β-gal and increased p16INK4A, have been
reported in age-​related neurodegenerative disease.
Several therapeutic strategies aim to target these
senescence markers. For example, some drugs, including
rapamycin, melatonin, resveratrol, metformin and
oestrogen, can suppress the SASP in senescent cells. This
process does not induce cell death or alter cell numbers.
Another strategy is to induce cell death, which includes
apoptosis and immunotherapy. Senolytics (drugs that
preferentially kill senescent cells), FOXO4 peptide and
inhibitors of BCL-​W and BCL-​X induce apoptosis in
senescent cells. Immunotherapy is another promising
strategy for removing senescent cells from the brain and
other tissues, and rejuvenation of senescent cells is
currently under investigation as another treatment for
age-​related pathologies. DDR , DNA damage responses.
senescent cells from AD mice helps reduce neuroinflam-
mation and Aβ accumulation and improves cognitive
deficits119. Tau pathology can also induce neuronal and
glial senescence120. Interestingly, treatments that remove
senescent cells in the brain can be neuroprotective, as
they can prevent tau-​dependent pathology and cognitive
decline117,118.
Nutritional and metabolic factors might also be risk
factors for AD. For example, calorie restriction can
have neuroprotective effects56, and insulin and IGF1
resistance in the brain is an early and common feature
of AD121. mTOR signalling is upregulated in AD, and
mTOR inhibitors, such as rapamycin, can improve AD
pathology, including cognitive deficits122. AMPK signal-
ling regulates tau phosphorylation and Aβ production
and is a potent activator of autophagy, which is down-
regulated in AD. However, although AMPK signalling
can delay the onset of AD, it might also increase neuro­
nal stress123. Additional studies have shown that brain
cells from AD models have reduced glucose and oxygen
metabolic rates124. AD neurons show reduced activity of
the glucose transporters GLUT1 and GLUT3 and the
glycolytic enzyme aldolase, causing glucose hypometa­
bolism and altered insulin signalling124, insulin resis­
tance, endoplasmic reticulum stress125, frequent type 2
diabetes, impaired fasting glucose and altered lipid
metabolism126. A decrease in hippocampal cholesterol
reduces Aβ formation in hippocampal neurons127.
Stem cell exhaustion and immune dysfunction are
also linked with AD. Exhaustion of CNS stem cells is
associated with poor cognitive ability, reflecting reduced
neurogenesis in the dentate gyrus, in patients with AD128.
Some evidence supports the therapeutic potential of
NAD+ supplementation in rescuing neurogenesis in AD
mice107. A GLP1 hormone analogue, liraglutide, has been
shown to prevent decline in hippocampal neurogene-
sis in an AD mouse model129. Exercise, omega-3 fatty
acid utilization, curcumin and flavanols have also been
reported to improve neurogenesis in AD models128.
Altered intercellular communication is observed
in brain tissue from patients with AD125. This finding
is consistent with the insulin resistance and increased
insulin receptor expression that is seen in brain tissue
from AD mice126,130,131. Peroxisome proliferator-​activated
receptor γ (PPARγ) agonists are well studied for their
role in peripheral metabolism, and also have therapeu-
tic potential in patients with AD via anti-​inflammatory,
anti-​amyloidogenic and insulin-​sensitizing effects132.
The anti-​diabetic drug metformin also has beneficial
effects on AD-​related pathology133. As mentioned ear-
lier, immune dysfunction and neuroinflammation are
features of AD pathology. Compared with brain tissue
from age-​matched control individuals, brain tissue from
patients with AD shows an increased number of acti-
vated microglia134. Aggregated Aβ fibrils in AD can
induce IL-1β secretion via NLRP3 inflammasome acti-
vation69. The identification of potential small-​molecule
compounds that reduce neuroinflammation might be an
effective strategy to combat AD.
Together, these findings suggest that ageing hall-
marks are all closely related to AD, and targeting of
one or more of these hallmarks might have therapeutic
potential.
Parkinson disease
PD is characterized by neuronal loss in the substantia
nigra, causing striatal dopamine deficiency, and by intra-
cellular inclusions containing aggregates of α-​synuclein.
Diagnostic features of PD include neuromuscular dys-
function that affects movement amplitude and speed,
rigidity and/or rest tremor. The molecular pathogene-
sis of PD involves multiple pathways and mechanisms,
including α-​synuclein proteostasis, oxidative stress,
mitochondrial function, calcium homeostasis, axonal
transport and neuroinflammation10.
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Aggregates of α-​synuclein are found in neurons of
all patients with PD. Soluble α-​synuclein monomers ini-
tially form oligomers, and then combine to form small
and eventually large insoluble α-​synuclein fibrils, which
are neurotoxic and associated with cytoplasmic inclu-
sions known as Lewy bodies135. α-​Synuclein aggregation
and mitochondrial dysfunction seem to be synergistic
features of PD, and mitochondrial dysfunction has been
suggested to promote α-​synuclein aggregation in degen-
erating neurons of patients with PD136. Reducing the
activity of mitochondrial complex 1 (part of the electron
transport chain) and PPARγ co-​activator 1α (PGC1α)
leads to mitochondrial dysfunction and oxidative stress
in PD136,137. Post-​mortem brain imaging and biomarker
studies strongly suggest that neuroinflammation is
prominent in brain tissue from patients with PD138.
DNA repair defects can impair function of the dopa-
minergic axis, thus increasing the risk of PD139. Several
studies have shown that telomere shortening is also
involved in the pathogenesis of PD25. Epigenetic alter-
ations, including increased methylation of promoter
regions and histone modifications, have also been
reported in PD140. Protein ubiquitination occurs at a
higher level in cells from PD patients than in cells from
normal controls28.
Mutations in PINK1 or PRKN (the gene encoding the
protein Parkin) are also associated with PD32. A mouse
study has suggested that mitophagy, which is at least in
part mediated by the PINK1–Parkin pathway, mitigates
PD33. Genetic and pharmacological induction of NIX-​
dependent mitophagy might have therapeutic potential
for PD35.
With respect to cellular senescence, deposition of
α-​s ynuclein in PD is linked with increased senes-
cence, and increased abundance of senescent cells and
increased expression of SA-​β-gal are observed in brain
tissue from PD patients114.
Regarding deregulated nutrient sensing, targeting of
mTOR and AMPK also has a protective role in PD141.
Brain cells from AD, PD and HD models show reduced
glucose and oxygen metabolic rates124. Brain cells from
patients with PD also show dysglycaemia126. Mutations
in GBA1, SMPD1 or SREBF1 increase lipid accumulation
and are associated with a high risk of PD142.
Neurogenesis decreases in the early stages of PD143.
Transplantation of iPSC-​derived dopaminergic neurons
has shown promising results in a primate model of PD144.
Considering neuroinflammation, activation of microglia
and sustained elevation of pro-​inflammatory mediators
are associated with PD145. The mutant α-​synuclein in PD
is also capable of inducing IL-1β secretion via NLRP3
inflammasome activation70.
Other neurodegenerative diseases
This Review focuses mainly on AD and PD because
they are the most prevalent neurodegenerative diseases.
Other neurodegenerative diseases that have important
links with ageing, including ataxia telangiectasia, ALS,
HD and Cockayne syndrome (Table 1), are discussed
briefly here.
Ataxia telangiectasia is a rare, complex genetic neuro­
degenerative disorder caused by mutations in ATM,
Nature Reviews | Neurology
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which encodes a master regulator of the DDR signal-
ling pathway. Ataxia telangiectasia is characterized by
progressive cerebellar degeneration, immunodeficiency,
radiation sensitivity, diabetes, progressive dysarthria,
choreoathetosis, cancer predisposition, and features of
premature ageing146. Cerebellar atrophy, especially the
loss of Purkinje cells and granule cells, is thought to
lead directly to neurodegeneration in this disorder147.
Although this process is not well understood, high
levels of DNA damage and ROS and/or mitochon-
drial dysfunction are proposed to have key roles in the
pathophysiology of ataxia telangiectasia148,149. Given
the importance of ATM in DDR signalling, the patho-
genesis of ataxia telangiectasia illustrates how accelerated
accumulation of DNA damage might result in ageing
and neurodegeneration. Thus, this disorder serves as a
good model to dissect the mechanisms of ageing and
neurodegeneration.
ALS is characterized by deposition of TAR DNA-​
binding protein 43-positive protein inclusions and by
defects in several pathways, including protein homeo­
stasis, nucleocytoplasmic and endosomal transport,
endosomal and vesicular transport, axon structure
and function, DNA repair, oligodendrocyte function,
neuroinflammation and mitochondrial function150.
HD pathology is linked with cytotoxic forms of hun-
tingtin protein, which lead to global cellular impair-
ments including synaptic dysfunction, mitochondrial
toxicity and decreased rates of axonal transport151.
Cockayne syndrome is characterized by severe neuro­
degeneration, accelerated ageing, DNA repair defects,
transcription defects and mitochondrial dysfunction152.
Some studies have shown an increased frequency of
mitochondrial dysfunction and oxidative DNA dam-
age in motor neurons from patients with ALS or ataxia
telangiectasia146,153. Premature ageing diseases associated
with DNA repair defects, including ataxia telangiecta-
sia and xeroderma pigmentosum groups A and F, are
accompanied by neurodegeneration, suggesting a corre-
lation between DNA damage and neuronal dysfunction.
Telomere shortening is also associated with neurodegen-
erative diseases154–156. The HD locus maps to within 325 kb
of the end of chromosome 4p, suggesting that ageing-​
related telomere attrition could affect its transcription
or function. Shorter telomeres have also been linked
with earlier onset of pathology in a mouse model of
ALS155. In HD, transcriptional dysregulation is thought
to precede onset of massive neuronal cell death 108.
Increased protein ubiquitination has also been observed
in cells from patients with HD or ALS28.
Antagonistic hallmarks of ageing, such as mitochon-
drial dysfunction and deregulated nutrient sensing,
are also involved in these other neurodegenerative dis-
eases. For example, mitophagy mitigates inflammation,
thereby decreasing the risk of neurodegenerative dis-
eases. In addition, patients with HD present with low
cholesterol levels and are also at increased risk of type 2
diabetes;126,157 mutant huntingtin accumulates in the
pancreas and can decrease insulin secretion.
Integrative hallmarks of ageing are also risk factors
for other neurodegenerative diseases. Neurogenesis in
the dentate gyrus is reduced in patients with HD and
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can be rescued by exercise, omega-3 fatty acid utiliza-
tion, curcumin and flavanols128. The ATM protein is
essential during adult neurogenesis158; however, stem
cell therapy for ataxia telangiectasia may be associated
with poor outcomes, as a patient developed multifocal
brain tumours159. Nevertheless, targeting of aged stem
cell regeneration might alleviate some age-​associated
neurogenerative diseases in the future.
A correlation between neuroinflammation and neuro­
degenerative disease has been shown many times.
Chronic inflammation, persistent activation of micro-
glia, sustained elevation of pro-​inflammatory mediators,
and increased oxidative stress are seen in brain tissue
from patients with HD160 and spinal cord tissue from
patients with ALS161. Studies have shown that the mutant
huntingtin in HD and mutant SOD1G93A in familial ALS
can induce IL-1β secretion through NLRP3 inflamma­
some activation71–73. Inhibition of inflammation has been
shown to prevent the progression of ataxia telangiectasia
symptoms in ATM-​deficient mice162. Metabolic repro-
gramming is sometimes initiated when cells need to sup-
port and respond to defective signalling networks; for
example, glutamine metabolic rewiring and glutamine
supplementation might have roles in ataxia telangiec-
tasia163,164. Chronic inflammation contributes to tissue
reprogramming, which is itself the result of metabolic
reprogramming. These findings suggest that regulation
of the immune system could have therapeutic benefits
in neurodegenerative diseases.
Therapeutic approaches
Potential treatment options for neurodegenerative dis-
eases related to ageing and hallmarks of ageing include
NAD+ supplementation, induction of mitophagy, inhi-
bition of cellular senescence, and targeting of protein
aggregation, metabolism or inflammation.
NAD+ supplementation
NAD+ is a key cofactor in the cellular redox reactions
involved in cellular energy metabolism and other bio-
logical processes23. An adequate cellular level of NAD+ is
required for mitochondrial health, energy homeostasis,
stem cell renewal, DNA repair, neurological function
and resistance to cellular stress23. NAD+ is a cofactor for
sirtuin deacetylases and cyclic ADP-​ribose hydrolases,
and is the ADP-​ribose donor for the DNA repair protein
PARP1 (ref.23).
NAD+ levels decrease with age in many different
species including yeast, D. melanogaster, mice and
humans23. NAD+ precursors (such as nicotinamide ribo-
side and nicotinamide mononucleotide (NMN)), NAD+
biosynthetic enzymes (such as NAMPT activators) and
NAD+ degradation inhibitors (such as CD38 inhibitors
and PARP inhibitors) can increase the level of NAD+
(ref.165). Exogenous dosing with compounds that increase
the endogenous pool of NAD+ (for example, nicotina-
mide riboside and NMN) might improve lifespan and
healthspan and delay the onset or ameliorate patholog-
ical features of some ageing-​related diseases, including
AD and PD23,166. As an example, nicotinamide riboside
decreases tau phosphorylation and improves synaptic
and cognitive functions in 3×TgAD mice and in the
DNA repair-​deficient AD mouse model 3×TgAD/Polβ+/−
(ref.46). Nicotinamide riboside also improves learning
and memory in APP/PS1 mice23. NMN has similar
effects in mouse and rat models of AD23. Nicotinamide
riboside, NMN and other NAD+ precursors also reduce
inflammation in animal models of ataxia telangiectasia
and AD106,107,167. Nicotinamide riboside and P7C3, an
allosteric activator of NAMPT, have been reported to
have neuroprotective ability in AD and PD mouse mod-
els, respectively168. It has been proposed that endogenous
NAD+ protects against ageing-​related neurodegenerative
disease by promoting efficient DNA repair, autophagy,
mitophagy and mitochondrial health23. Nicotinamide
riboside and NMN are considered to show promise as
potential interventions for treating AD, PD, ALS, ataxia
telangiectasia and other neurodegenerative diseases23;
however, their potential has yet to be confirmed in
sufficiently powered clinical studies in humans. One
small study (in 30 patients) showed no statistically
significant benefit of nicotinamide on cognitive func-
tions in patients with mild to moderate AD169. Active
phase II and III trials of treatments targeting age-​related
disease mechanisms in patients with AD and PD are
summarized in Table 3.
Induction of mitophagy
Defects in mitophagy have been suggested to have a role
in the pathogenesis of AD and other neurodegenerative
diseases170. Agents that stimulate or rescue mitophagy
might have therapeutic potential in these diseases, a
possibility that has shown promise in various disease
models170.
Two classes of mitophagy-​stimulating molecules
are known. One type of agent promotes mitophagy by
inducing mitochondrial damage, making these agents
unsuitable as human therapeutics because of their tox-
icity. Such molecules include mitochondrial uncouplers
(such as FCCP and CCCP, which induce mitochondrial
depolarization), respiration-​damaging reagents (such
as antimycin A), oligomycin and superoxide reagents
(such as diquat and rotenone). A second group of agents,
which include resveratrol and NAD+ precursors, pro-
mote mitophagy without interfering with mitochondria.
The pleiotropic effects of these compounds include acti-
vation of sirtuin 1 (ref.171). This second group of mito-
phagy inducers could be developed as potential drugs
for neurodegenerative diseases. In C. elegans, NAD+
precursors activate the DCT1 pathway, increase mito-
phagy and improve the lifespan and healthspan of atm-​
null worms106. Resveratrol reduces β-​secretase activity
and Aβ peptide aggregation in AD models and has
shown neuroprotective effects in models of AD, PD and
HD172. Another more specific mitophagy-​stimulating
compound, urolithin A, a metabolite compound trans-
formed from ellagitannins by gut bacteria, has shown
promising results in C. elegans models of ageing-​related
neurodegeneration, where it normalized defects in
mobility and pharyngeal pumping170. Urolithin A has
also shown beneficial effects on learning and memory in
the APP/PS1 mouse model111. In rats, urolithin A lacked
toxic adverse effects after oral dosing for 90 days173,
which has increased interest in its therapeutic use.
www.nature.com/nrneurol
 Reviews

Table 3 | Active phase II/III clinical trials targeting age-​related disease mechanisms in AD and PD
Target Mechanisms of Drug Disease estimated Clinicaltrials.
action (n) termination gov
date identifier
Metabolism Cell signalling and cell Insulin AD (30) September 2019 NCT02462161
growth
AD (90) May 2019b NCT02503501
Glucagon-​like peptide-1 AD (206) December 2019 NCT01843075
agonists (liraglutide,
semaglutide) PD (57) December 2020 NCT02953665
PD (120)a December 2024 NCT03659682
Mitochondrial Antioxidant; autophagy Nicotinamide (vitamin B3) AD (48) June 2020 NCT03061474
function induction; DNA repair
induction; histone PD (200)a October 2021 NCT03568968
deacetylase inhibition N-acetylcysteine, l-carnitine AD (60), September 2020 NCT04044131
(inhibition of tau tartrate, nicotinamide PD (60)a
phosphorylation); riboside and serine
anti-​inflammatory
S-equol AD (40) October 2019 NCT03101085
Niacin PD (80) September 2019 NCT03462680
Resveratrol AD (48) October 2019 NCT02502253
Grape powder AD (32) May 2019 NCT03361410
Tyrosine kinase Nilotinib PD (135) October 2020 NCT03205488
inhibitor
AD (42) February 2020 NCT02947893
Inflammation Angiotensin-​II Telmisartan AD (240) March 2021 NCT02085265
receptor blocker
Candesartan AD (72) September 2021 NCT02646982
Anti-​viral Valacyclovir AD (130) August 2022 NCT03282916
Anti-​inflammatory Salsalate (salicylic acid) AD (40) October 2019 NCT03277573
Mast cell and ALZT-​OP1 (cromolyn, AD (600) November 2019 NCT02547818
macrophage inhibition ibuprofen)
Trials targeting protein aggregation as the primary mechanism and trials only evaluating bioavailability , biomarkers and safety are
not mentioned here. Reference: www.clinicaltrials.gov August 2019. AD, Alzheimer disease; PD, Parkinson disease. aNot yet
recruiting. bActive, not recruiting, results not yet published.

Lifestyle modifications that protect against ageing-​
related neurodegeneration, including exercise and cal-
orie restriction, also increase mitophagy; however, this
effect is likely to be indirect, instead reflecting a complex
multifaceted organismal response174.
Inhibition of cellular senescence
Studies have shown that mTOR is a crucial biochemical
modulator of ageing and promotes SASP175. Inhibition
of prosenescent mTOR signalling with rapamycin decel-
erates cellular senescence in the ageing brain, perhaps
by combining its multiple neuroprotective effects with
suppression of cellular senescence176.
Metformin has been shown to suppress cellular
senescence via activation of microRNA-​processing
proteins and to prevent amyloid plaque deposition and
α-​synuclein phosphorylation in AD and PD, respec-
tively177,178. In a tau-​overexpression neurodegeneration
mouse model, increased numbers of senescent astro-
cytes and microglia were associated with an increase in
the deposition of tau NFTs, whereas clearance of these
cells prevented tau-​dependent pathology and cognitive
decline118. Senescent astrocytes or microglia accumulate
with ageing and have been detected in patients with AD,
PD and ALS114,115, so removal of senescent cells might
provide a novel therapeutic approach to the treatment
of age-​related neurodegenerative diseases179 (Fig.  5).
Elimination strategies using FOXO4 peptide treatment,
inhibition of BCL-​W and BCL-​X, and immunotherapy
all had beneficial effects on age-​related dysfunction
in animal models180. From these findings, inhibition
of SASP, elimination of senescent cells and reversal of
cell senescence might all represent effective anti-​
ageing treatments and innovative strategies for treating
neurodegenerative diseases.
Targeting protein aggregation
Protein aggregation is a prominent feature of AD
and other neurodegenerative diseases, as described
above181,182. Therefore, several therapeutic approaches
for AD aim to reduce the abundance of Aβ aggregates
via immunotherapy or by inhibiting γ-​s ecretase or
β-​secretase84. Multiple therapies of this type, investigated
over 10–20 years, have produced disappointing results.
Other strategies targeting tau aggregates and NFTs183,
which are associated with several neurodegene­rative
disorders, including AD, frontotemporal lobar degene­
ration, progressive supranuclear palsy, corticobasal
degeneration and Pick disease, are under investiga-
tion93,184. Very few phase III clinical trials testing tau as a
therapeutic target for AD are currently in progress, but
many phase II trials targeting tau pathology in AD are
moving through the pipeline185. As these studies pro-
gress, it will become clearer whether strategies targeting

Nature Reviews | Neurology

Reviews

tau aggregates have therapeutic benefit for any of the
neurodegenerative diseases.
Targeting metabolism and inflammation
Human and animal studies have shown that dysregu-
lation of insulin signalling contributes to ageing and
increases susceptibility to neurodegenerative diseases.
Consistent with this idea, some antidiabetic compounds
are neuroprotective and improve cognitive function133,186.
So far, the most promising treatments have involved
administration of thiazolidinediones, especially pioglita-
zone186 in AD, but ongoing clinical trials are also testing
the efficacy of insulin and glucagon-​like peptide-1 in AD
and PD (Table 3).
Neuroinflammation is a major pathophysiolog-
ical feature of neurodegenerative disorders. Anti-​
inflammatory interventions have, however, been largely
ineffective, although ibuprofen might reduce the risk
of developing PD187,188. In a recently completed trial
(NCT02588677), the tyrosine kinase inhibitor mas-
itinib showed promising effects in patients with ALS189.
Masitinib targets mast cells and macrophages by inhib-
iting a number of protein kinases and also targets micro-
glia and inhibits inflammatory processes within the
CNS. Trials investigating other anti-​inflammatory drugs
as therapies for ALS have shown negative results190.
Other therapeutic approaches
Other pharmacological interventions for neurological
diseases target various cellular processes or molecules
that promote or delay ageing, including calorie restric-
tion, oxidative stress, telomerase, autophagy, stem cell
renewal and epigenetic mechanisms.
Calorie restriction increases lifespan in multiple
species by modulating AMPK, IGF1 and mTOR signal-
ling pathways and the processes they regulate including
nutrient sensing, autophagy, mitochondrial function and
cell proliferation. Some compounds, including 2-deoxy-​
d-glucose and resveratrol, mimic the beneficial effects of
calorie restriction.
Many antioxidants are thought to be neuroprotective,
including vitamin E, quercetin, N-​acetyl-l-​c ysteine,
curcumin, carotenoids, flavonoids, isothiocyanates,
terpenoids, proanthocyanidins, omega-3 fatty acids,
melatonin and coenzyme Q10 (CoQ10)191. Low CoQ10
levels have been observed in patients with PD, HD
or Friedreich ataxia (another debilitating neurolog-
ical movement disorder)192. However, clinical trials of
CoQ10 supplementation have shown limited efficacy
in patients with AD, PD or ALS192. Cyclic GMP–AMP
synthase (cGAS) is a DNA sensor that triggers innate
immune responses mediated by the secondary messen-
ger cyclic GMP–AMP, which binds and activates the
adaptor protein STING. A 2018 study suggested that
genomic instability and DNA damage activate cGAS,
linking DNA damage with inflammation, cellular senes-
cence and cancer193, but a link between cGAS and AD
has not yet been investigated. The therapeutic potential
of targeting the STING pathway in neurodegeneration
is currently under investigation33.
Conclusions
Efforts to develop evidence-​based treatment strategies
for neurodegenerative diseases are ongoing, but nei-
ther highly effective treatments nor potent protective
approaches have yet been identified. In the future, more
studies on neurodegenerative diseases should focus
on the nine hallmarks of ageing, most of which show
associations with neurodegenerative diseases. Among
these hallmarks, those relating to DNA damage and
mitochondrial dysfunction are central, and studies
investigating communication between the nucleus and
mitochondria will contribute to a mechanistic under-
standing of ageing and the pathogenesis of neuro­
degenerative diseases. Although in the present Review
we narrow our focus to aspects of DNA damage, mito-
chondrial dysfunction, cellular senescence and inflam-
mation, which are frequently considered to be causes of
neurodegeneration, other ageing-​related hallmarks are
also important in neurodegenerative disease and the dif-
ferent hallmarks are highly interconnected. For example,
the loss of proteostasis owing to defects in proteasome or
autophagy observed in AD and PD is strongly related to
inflammation and senescence13,194. Metabolic dysfunc-
tion observed in neurodegeneration is associated with
alterations in NAD+ levels, mitochondrial dysfunction
and oxidative stress57. Loss of functional stem cells is
related to almost all of the ageing hallmarks, includ-
ing DNA damage, epigenetic deregulation, mitochon-
drial dysfunction, telomerase inactivation and cell
senescence58.
Given the complex nature of neurodegenerative
diseases, and the fact that genetic and environmental
factors can determine disease progression, single-​drug
or single-​pathway-targeted approaches might be inad-
equate — more holistic approaches or combined treat-
ment strategies might be necessary and more likely to
succeed. The association between neurodegenerative
diseases and ageing hallmarks could bring new hope for
the treatment of such diseases. Multi-​targeted pharma-
ceutical evidence-​based approaches might need to be
combined with non-​pharmacological approaches and/or
lifestyle modification in order to slow the epidemic of
neurological disease in elderly individuals.
Published online xx xx xxxx

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Acknowledgements
The authors’ research is supported by the Intramural
Research Program of the NIH National Institute on Aging. The
authors thank B. Yang and N. B. Fakouri for critical reading of
the manuscript. The Bohr laboratory receives nicotinamide
riboside as a gift from ChromaDex.
Author contributions
All authors researched data for the article, Y.H., X.D., M.B.,
Y. W., D.L.C. and V.A.B. contributed substantially to the dis-
cussion of content, Y.H., X.D., M.B., Y.W., S.G.H., D.L.C. and
V.A.B. wrote the article, and Y.H. and V.A.B reviewed
and edited the manuscript before submission.
Competing interests
The authors declare no competing interests.
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