With a referendum on Scottish independence now agreed, Scottish nationalists can dare to wonder: what would an independent Scotland look like? Alex Salmond naturally has plenty of suggestions. Two adjectives he is unlikely to choose are "unhealthy" and "shortlived" – but, as delegates at Scotland's annual public health conference will hear this week, the poor health of Scotland's citizens remains a matter of profound concern. With the lowest life expectancy in western Europe, Scotland has been in the grip of a public health crisis for decades now. And ground zero for that crisis is unquestionably the country's largest city: Glasgow.

Whether it is deaths from cirrhosis, drug abuse, lung cancer, murder or suicide, Glasgow's mortality rates are easily the highest in Britain, and among the highest in Europe. Life expectancy at birth in Glasgow is the lowest in the UK – more than six years below the national average for Glaswegian men (71.6 years, compared with a UK average of 78.2 years), and more than four years below average for Glasgow's women (78 years, compared with the UK average of 82.3). And because Glasgow is home to more than 10% of Scotland's total population, with nearly 600,000 people in the city itself, and more than a million in the greater Glasgow area, Glasgow's problems are very much Scotland's problems.

"It's a human tragedy on a massive scale," says Gerry McCartney, an epidemiologist at NHS Scotland. His colleague, David Walsh, a lead researcher at Glasgow Centre for Population Health adds: "You are talking about thousands of people dying before their time."

Stand in the bustling centre of Buchanan Street on a sunny autumn afternoon, and you would be hard pressed to spot signs of a public health emergency in Glasgow. Shoppers stream past the pristine sandstone shopfronts, looking every bit as prosperous and confident as Salmond could wish for – and no less healthy than people anywhere else in Britain. Walk a few miles east, however, and the dire statistics become easier to believe. Glasgow's city boundaries contain some of Britain's most deprived neighbourhoods.

"You don't need to be a doctor to see how unhealthy people in these communities are," says Dr Saket Priyadarshi, a senior GP in Glasgow's addiction services, who has spent most of his professional life treating addicts in the city's east end. He is not exaggerating. Pale men cluster outside windowless pubs puffing on cigarettes. A frail couple, three crutches between them, totter out of an off-licence, pausing to adjust the large plastic cider bottles in their backpacks. An obese man with a withered leg limps down Tollcross Road, eating pizza from a cardboard box.

Yet, the conventional wisdom that Glasgow's ill health is all down to poverty, bad diet and bad behaviour is, at best, partial and, at worst, misleading. Despite years of research and decades of evidence that something has gone terribly wrong in the heart of Scotland's largest city, the underlying causes of Glasgow's fatally poor health remain something of a scientific mystery.

Poverty alone doesn't account for Glasgow's dismally low life expectancy. Other British cities – Liverpool and Manchester, for example – have rates of deprivation every bit as high as Glasgow, yet their life expectancies are substantially higher. What's more, even Glasgow's most affluent citizens, those in the top 10% of the income distribution, die significantly younger than their counterparts in other British cities. At best, according to the epidemiologists' calculations, deprivation accounts for less than half (around 40%) of Glasgow's "mortality gap" compared with the rest of the UK. The other causes are still unknown.

Epidemiologists call it "the Glasgow effect", which sounds reassuringly scientific, but, as Walsh readily concedes, it is nothing more than a label scientists have chosen for their ignorance.

"The use of that word ['effect'] excites people," he laments. "They start saying 'because of the Glasgow effect …' as though we know what it is. The whole point is – it's something we don't know the answer to."

With colleagues at NHS Scotland and the University of Glasgow, Walsh has devoted much of the past five years to uncovering what makes Glasgow so different, compared with other, similarly deprived British cities. If you think deep-fried Mars bars are to blame for Glasgow's ill health (as many English commentators seem to), then think again: obesity rates in the city are actually lower than in some English cities.

Nor can Glasgow's infamous penchant for alcohol and cigarettes explain the puzzle. According to the largest health surveys in England and Scotland, Glaswegians neither binge-drink nor smoke more than their peers in Liverpool or Manchester. Drug abuse (particularly heroin), knife crime, murder and suicide are all significantly more prevalent in Glasgow than in other cities. But that only prompts the question – why is this the case? What is it about life in Glasgow that seems to predispose some of its citizens to such destructive behaviours?

"Lots of people have their own pet hypotheses about it," Walsh says. In a recent research paper, Walsh, McCartney and their co-authors, Chik Collins and David Batty, assessed no fewer than 17 competing explanations for Glasgow's ill health. There are theories that blame the weather (perhaps it is vitamin D deficiency or chilly winters?), those that blame the data (perhaps Glasgow is simply poorer than it looks?), plenty of theories that blame the Glaswegians (a culture of hedonism, sectarianism or alienation) and still others that point the finger at the Tories (a "political attack" on Glasgow, conducted by Margaret Thatcher's government). Some have more supporting evidence than others, but all are unproven, says Walsh. "The main thing to say is that it's not going to be one thing. It's going to be a combination of different factors interacting," he says.

This leaves Scotland's policymakers in something of a quandary: how can you tackle a problem when you don't know what is causing it? The answer so far has been to bring in increasingly heavy regulation of unhealthy choices. In recent years, Scotland has become a trailblazer for public health regulations. The country was the first in Britain to ban smoking in public places, and hopes to become the first to introduce a minimum unit price for alcohol.

These policies are wholeheartedly welcomed by Dr Linda de Caestecker, director of public health for NHS Greater Glasgow and Clyde. She has pressed for restrictions on the opening of new bars and off-licences, and on the serving of unhealthy food in schools and public buildings, and is pondering whether councils might restrict the opening of fast-food restaurants near Glasgow's schools. "I get accused of being sort of 'regulation for everything'," De Caestecker notes, drily. "But at the very least we need to make the healthy choices cheaper than the unhealthy choices."

Scotland's approach to tackling deaths from violent crime has been rather more creative. A decade ago, Glasgow languished as "the murder capital of western Europe", with rates of knife crime and homicide more than double those in London, but its homicide rate has fallen by a third since the early 2000s, and violent crime is also decreasing.

The city's innovative Violence Reduction Unit (VRU), established by Strathclyde police in 2005, can claim a large share of the credit, having piloted a range of unorthodox strategies to cut violent crime . These include giving police officers full-time posts on school campuses, bringing violent gangs into court en masse to confront the communities they terrorise, and training dentists and vets to recognise the signs of domestic abuse. "We took the attitude that it's so big and so complex, it doesn't make any difference where you start," says VRU co-director, detective chief superintendent John Carnochan, candidly. "Just make a bloody start."

All of which makes Glasgow's dismal life expectancy all the more demoralising. If Scotland is to fulfil its potential – whether independently or as part of the UK – then Glasgow needs to heal. But, for now, social scientists continue to juggle dozens of different research projects, all aimed at uncovering the causes of the city's malaise. Scotland's policymakers can only hope they succeed – and the sooner the better.