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ASHINGTON — Marco Rubio, the fresh-faced senator from Florida, has made more than a few passing references to the advanced age of some of his presidential campaign rivals. Now he’s ready to use his youth as a bludgeon.

After the 69-year-old Donald Trump tweeted that the 44-year-old Rubio “looks like a little boy on stage,” Rubio finally took the issue head on.

“I wouldn’t even be the youngest person ever president. He would be the oldest person ever president, which is a problem because you could serve, like, eight years,” Rubio said at a rally Friday in Oklahoma City. “You know, you start to worry a little bit, all right?”

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With that remark, Rubio officially called Trump an old dude — and stepped into the sensitive politics of age in presidential campaigns.

In an election in which nothing’s really over the line anymore, Rubio’s bit of snark is unlikely to be the last when it comes to the issue of age. It’s likely that the front-runners for the Republican and Democratic nominations after Super Tuesday contests will be 69-year-old Trump and 68-year-old Hillary Clinton. Even then, Clinton could still be in for a long battle with 74-year-old Bernie Sanders, who’s not going away soon.

History is rife with examples of candidates who have sought to make age a factor in elections — sometimes to great effect, and other times not so much. Here’s a look at how the issue has played in past campaigns:

When the age issue sticks and when it doesn’t

It’s not that the age of a presidential candidate in itself matters most to voters. It’s whether there are obvious health problems that go with it.

When Ronald Reagan ran in 1980, he was 69 — the oldest person elected to the presidency. But his age didn’t make a difference to voters because his ads showed him on horseback, full of energy and life, according to Robert Blendon, a health care public opinion expert at Harvard University who directs the STAT-Harvard polls on medical science issues.

“Nobody thought Reagan was too old … Reagan could have won a third term,” said Blendon. Even now, he said, “you see all these young people following Bernie Sanders around. It’s incredible.”

The lesson, he said, is that “the health condition is the issue, not the age.”

The Trump campaign declined to respond to Rubio. Trump, Clinton, and Sanders have all tried to put questions about their health to rest by releasing summaries of their medical records — though in Trump’s case, the letter mostly drew snickers from medical experts as it predicted he would be “the healthiest individual ever elected to the presidency.”

They also don’t go into a lot of detail. Although the letter from Clinton’s physician addresses the concussion she suffered in December 2012, Trump’s letter doesn’t suggest that he has any health problems at all — or ever has in the past, for that matter.

The age issue did stick with Bob Dole — especially when the then 73-year-old fell off a stage in California, inadvertently reviving the issue and sending his aides scrambling to control the damage. When a poll by the Pew Research Center for the People and the Press asked voters to choose one word to describe Dole, the top choice was “old.”

And Franklin D. Roosevelt was vulnerable when he ran for a fourth term in 1944 — not because the 62-year-old Roosevelt was old by today’s standards, but because he looked sick and frail. His Republican opponent, Thomas Dewey, even charged that Roosevelt was a “tired old man” with “tired old men” in his cabinet. It didn’t work, though: Roosevelt crushed Dewey at the polls.

Health is more than age, of course. John F. Kennedy, at 43, was the youngest person ever elected to the presidency (the minimum age is 35). But he had suffered from Addison’s disease for 15 years before the 1960 election. His campaign managed to keep the issue under wraps, even though Kennedy had to take steroid and other drugs to overcome symptoms from the autoimmune disorder.

Roosevelt also sought to sanitize his public image, and any health concerns, by avoiding having pictures taken while in the wheelchair that polio had forced upon him.

Disclosure does have risks. After George McGovern picked Thomas Eagleton to be his running mate in 1972, rumors began to circulate about Eagleton’s mental health. He acknowledged to the media that he had been hospitalized for depression multiple times. The issue didn’t go away and McGovern soon dropped Eagleton from the ticket.

Backlash against Obama

There’s also a big problem with raising age directly: It’s just as likely to backfire against a candidate.

“It’s acceptable to say we view the world differently,” Carter Eskew, a senior adviser to Al Gore’s 2000 presidential campaign, told STAT. “It’s not acceptable to say you’re an old bag.”

President Obama’s campaign made a pretty direct attack on McCain, who was 72 when he ran for the White House in 2008 — and suffered a bit of backlash.

In the Obama ad, called “Computer,” the narrator said McCain “admits he doesn’t know how to use a computer, can’t send an e-mail.”

“Things have changed in the last 26 years,” the ad said, since the Arizona senator had come to Washington. “But McCain hasn’t.”

The Obama campaign asserted it wasn’t an age-based attack, but still faced criticism — exacerbated by the fact that McCain’s war injuries had made it harder for him to use some technology.

Even Joe Biden, by then Obama’s running mate, called the ad “terrible.”

Delicacy, instead, seems to be the best policy, even if a candidate’s criticism still subtly brings an opponent’s age into play.

Take how Clinton handled Dole’s age, which had become a recurring issue in news coverage during the 1996 campaign, in one memorable moment. Dole had responded to a debate question about his age by saying “it is also a strength, an advantage. I think wisdom comes from age.”

“I don’t think Senator Dole is too old to be president,” Clinton replied. “It is the age of his ideas I question.”

USA Today later called it Clinton’s best line of the campaign.

The best defense: jokes

Humor might be the best — and only — weapon for older candidates.

Sanders has tried, though at times he has sounded defensive in the process. When CNN anchor Chris Cuomo said at an Iowa town hall in January that Sanders was “going on 75,” Sanders corrected him loudly: “I’m going on 75? So are you! You’re going on 75.”

Others have fired back more successfully. Reagan famously put the issue to rest in a 1984 debate against Democratic nominee Walter Mondale by saying he refused to exploit “my opponent’s youth and inexperience.” (Mondale was 56 at the time.)

Dole was often defiant about his age, arguing throughout the campaign that he was healthy and capable. He put out a clean bill of health, from his doctor, in what has become a campaign ritual.

But as the issue stuck, and some polls found almost one-third of Americans thought he was too old to be president, Dole tested out a little humor too.

“You always feel a little older in the morning. By noon I’ll feel 55,” he said during one campaign stop — a none-too-subtle nod to his 50-year-old opponent.

And in 2008, McCain was never going to win a generational argument against a candidate who was a quarter-century younger than he was. But he did try to neutralize the age question in a faux-commercial on “Saturday Night Live.”

“I ask you: What should we be looking for in our next president?” McCain said to the audience at the start of a three-minute spot. “Certainly, someone who is very, very, very old.”

He got big laughs.

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