I'm a clinician rather than a building-envelope specialist, but I see the downstream health impact of poorly-sealed older homes in patients regularly -- sleep disruption from drafts in the bedroom, respiratory irritation from outside-air infiltration during high-allergen days, and the cumulative stress of an indoor environment that doesn't hold a stable temperature.
The single principle I'd recommend for deciding which gaps to seal first: prioritize the rooms used during sleep and during the most cognitively-demanding work, and within those rooms prioritize the gaps closest to where the occupant actually sits or lies down. The room-by-room return on sealing varies dramatically, and the highest-return gaps are the ones whose drafts an occupant feels directly during the hours that matter most for sleep quality and cognitive function.
The specific technique that's worked best in my own home: a smoke pencil or stick of incense held near suspected gaps on a windy day. The smoke shows immediately where air is moving -- drafts at the window edges, gaps around recessed lighting in the ceiling, infiltration around outlets on exterior walls, and the bottom edges of doors that lead to unheated spaces. The smoke surfaces the gaps that are too small to feel by hand and would never be found by a visual inspection alone.
What I'd seal first in any older home: the gaps in the bedroom (highest impact on sleep), the gaps around the home's main work-from-home space (impact on cognitive function during the day), and any gaps connecting to unconditioned spaces like attics or basements (largest single source of conditioned-air loss).
What I avoid recommending: aggressive whole-house sealing without addressing ventilation simultaneously. A very-tightly-sealed older home with no ventilation strategy produces indoor-air-quality problems that may be worse than the heat loss the sealing was meant to address. The sealing strategy and the ventilation strategy have to be designed together.
For homes where the clinical signs of poor sealing show up in patients -- bedroom drafts disrupting sleep, allergen infiltration triggering respiratory symptoms, persistent cold spots producing discomfort -- the targeted seal-first-by-room approach produces real improvement quickly. The whole-house retrofit can come later if the budget supports it.