Table 2.

Pathways and risk factors common to multimorbidity and functional impairment: current knowledge

What we know	Knowledge gaps
Biological factors
• Old age, obesity, involuntary weight loss and sedentarism	• Specific biological mechanisms of ageing in
Pathway: All are risk factors for the burden and severity of	single individuals have not yet been identi
multimorbidity, probably because of their effect on levels of	fied
circulating inflammatory mediators (i.e. inflammaging) and thus	• Criteria to identify those forms of multi
on accelerated damage accumulation in organs and physiological	morbidity caused by accelerated biological
systems	ageing are lacking, which hampers the
• Ageing-related factors	development of targeted therapeutic and
Pathway: Intrinsic biological mechanisms of ageing (e.g. mito-	management interventions
chondrial dysfunction, cellular senescence, defective proteostasis)	• Specific clinical trials with outcomes related
could be the basis of the bidirectional association between	to the development and progression of mul
multimorbidity and functional impairment	timorbidity are still rare. An exception is the
• Epigenetic markers	future TAME study on chronic use of met
Pathway: Premature changes in epigenetic biomarkers (sensitive	formin [160]
to phenotypic deviations from normal biological ageing) are
associated with the severity of multimorbidity, providing further
support for the hypothesis that there is a link between the biology
of ageing and the risk for multimorbidity and functional impair-
ment
Care-related factors (i.e. drugs)
• Polypharmacy	• The need for and added value of preventive
Pathway: Drug-drug and drug-disease interactions and the pre	medicines in people with shortened life
scribing cascade (e.g. use of anti-Parkinson medication to treat	expectancy due to multimorbidity and/or
extrapyramidal symptoms caused by antipsychotics)	functional impairment is poorly understood
• Inappropriate use (e.g. anticholinergic drugs, proton pump	• The effectiveness of individual drugs in
inhibitors) or overuse (e.g. antidiabetics) of specific drugs	people with multimorbidity and/or func
• Lack of adherence to drug treatment	tional impairment, based on numbers
Pathway: Multimorbidity and functional deficits may limit	needed to treat, is little understood
patients’ ability to take medications accurately because of prob	• There is wide uncertainty about the impact
lems with pill handling. They may also affect decision-making and	of drug treatment on functional outcomes
reporting of adverse effects	(both physical and cognitive)
	• Few studies have addressed the bidirec
	tional association between sarcopenia and
	adverse drug events
Psychosocial factors
• Socioeconomic status	• The role of psychosocial factors in multi
Pathway: Less than half of the excess multimorbidity in deprived	morbidity, functional impairment and neg
populations is explained by lifestyle; the rest may be due to factors	ative outcomes needs to be better
such as adverse childhood experiences, negative life events, weak	delineated. Specifically, little is known
social networks and an external locus of control	about the direction of the associations and
• Psychological distress, social isolation, social conflict, emotional	potential moderating or mediating effects
isolation and lack of purpose in life	• Although there is some evidence that social
Pathway: The association between these factors and decline in	interventions such as social prescribing
physical and cognitive function in old age could be due to poor	may improve anxiety, depression and phys
self-management; amotivation; risk factors such as smoking,	ical activity [161], the influence of such
alcohol, poor diet and low exercise levels; and/or direct effects on	approaches on functional impairment or
inflammation	mortality is unknown
	• Clinical trials performed specifically on
	people living in deprived areas and incor
	porating modifiable psychosocial factors are
	rare. Recent primary care-based complex
	interventions focusing on priority goal set-
	ting [162] and patient-centredness [163]
	could serve as examples